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PubMed2002

A statistical model for the heterogeneous structure of porous catalyst pellets.

The complex structures of the void space of porous media are often characterised by parameters such as pore network connectivity and lattice size. This paper presents a comparison of the estimates of these parameters obtained from two previous methods based on nitrogen sorption and mercury porosimetry, and also from a new, completely independent approach based on pulsed-gradient spin-echo nuclear magnetic resonance (PGSE NMR). It was found that the new PGSE NMR technique obtains estimates of connectivity and lattice size in agreement with nitrogen sorption but different to mercury porosimetry. This difference was attributed to the various physical processes involved actually probing different aspects of the pore space geometry. It was further suggested that the representation of the pore structure derived from either nitrogen sorption or PGSE NMR is really a mapping of the real pore space onto an equivalent abstract, random pore bond network. However, it has been shown that this mapping does capture some of the characteristic properties of the pore space that control transport over mesoscopic ( < 10 microm) length scales. For materials which additionally possessed macroscopic (> 10 microm) structural heterogeneity, it was found that the model could also be adapted to predict the macroscopic transport properties of the porous medium.

Journal Article↗
PubMed2005

Systematic analysis of genes required for synapse structure and function.

Chemical synapses are complex structures that mediate rapid intercellular signalling in the nervous system. Proteomic studies suggest that several hundred proteins will be found at synaptic specializations. Here we describe a systematic screen to identify genes required for the function or development of Caenorhabditis elegans neuromuscular junctions. A total of 185 genes were identified in an RNA interference screen for decreased acetylcholine secretion; 132 of these genes had not previously been implicated in synaptic transmission. Functional profiles for these genes were determined by comparing secretion defects observed after RNA interference under a variety of conditions. Hierarchical clustering identified groups of functionally related genes, including those involved in the synaptic vesicle cycle, neuropeptide signalling and responsiveness to phorbol esters. Twenty-four genes encoded proteins that were localized to presynaptic specializations. Loss-of-function mutations in 12 genes caused defects in presynaptic structure.

Aldicarb↗
PubMed1991

Refined x-ray structure of papain.E-64-c complex at 2.1-A resolution.

E-64-c, a synthetic cysteine protease inhibitor designed from E-64, binds to papain through a thioether covalent bond. The x-ray diffraction data for 2.1-A resolution were used to determine the three-dimensional structure of this complex and refined it to R = 0.159. 0.159. In the complex structure, the configurational conversion from S to R took place on the epoxy carbon of E-64-c, implying that the nucleophilic attack of the Cys-25 thiol group occurs at the opposite side of the epoxy oxygen atom. The leucyl and isoamylamide groups of E-64-c were strongly fixed to papain S subsites by specific interactions, including hydrogen bonding to the Gly-66 residue. The carboxyl-terminal anion of E-64-c formed an electrostatic interaction with the protonated His-159 imidazole ring (O-...HN+ = 3.76 A) and consequently prevented the participation of this residue in the hydrolytic charge-relay system. No significant distortion caused by the binding of E-64-c was shown in the secondary structure of papain. It is important to note that inhibitor and substrate have opposite binding modes for the peptide groups. The possible relationship between the binding mode and inhibitory activity is discussed on the basis of the crystal structure of this complex.

Binding Sites↗
PubMedDate not supplied

The crystal structure of the complexes of concanavalin A with 4'-nitrophenyl-alpha-D-mannopyranoside and 4'-nitrophenyl-alpha-D-glucopyranoside.

Concanavalin A (Con A) is the best-known plant lectin and has important in vitro biological activities arising from its specific saccharide-binding ability. Its exact biological role still remains unknown. The complexes of Con A with 4'-nitrophenyl-alpha-D-mannopyranoside (alpha-PNM) and 4'-nitrophenyl-alpha-D-glucopyranoside (alpha-PNG) have been crystallized in space group P2(1)2(1)2 with cell dimensions a = 135.19 A, b = 155.38 A, c = 71.25 A and a = 134.66 A, b = 155.67 A, and c = 71.42 A, respectively. X-ray diffraction intensities to 2.75 A for the alpha-PNM and to 3.0 A resolution for the alpha-PNG complex have been collected. The structures of the complexes were solved by molecular replacement and refined by simulated annealing methods to crystallographic R-factor values of 0.185/0.186 and free-R-factor values of 0.260/0.274, respectively. In both structures, the asymmetric unit contains four molecules arranged as a tetramer, with approximate 222 symmetry. A saccharide molecule is bound in the sugar-binding site near the surface of each monomer. The nonsugar (aglycon) portion of the compounds used helps to identify the exact orientation of the saccharide in the sugar-binding pocket and is involved in major interactions between tetramers. The hydrogen bonding network in the region of the binding site has been analyzed, and only minor differences with the previously reported Con A-methyl-alpha-D-mannopyranoside complex structure have been observed. Structural differences that may contribute to the slight preference of the lectin for mannosides over glucosides are discussed. Calculations indicate a negative electrostatic surface potential for the saccharide binding site of Con A, which may be important for its biological activity. It is also shown in detail how a particular class of hydrophobic ligands interact with one of the three so-called characteristic hydrophobic sites of the lectins.

Binding Sites↗
PubMed1994

Structures of ternary complexes of rat DNA polymerase beta, a DNA template-primer, and ddCTP.

Two ternary complexes of rat DNA polymerase beta (pol beta), a DNA template-primer, and dideoxycytidine triphosphate (ddCTP) have been determined at 2.9 A and 3.6 A resolution, respectively. ddCTP is the triphosphate of dideoxycytidine (ddC), a nucleoside analog that targets the reverse transcriptase of human immunodeficiency virus (HIV) and is at present used to treat AIDS. Although crystals of the two complexes belong to different space groups, the structures are similar, suggesting that the polymerase-DNA-ddCTP interactions are not affected by crystal packing forces. In the pol beta active site, the attacking 3'-OH of the elongating primer, the ddCTP phosphates, and two Mg2+ ions are all clustered around Asp190, Asp192, and Asp256. Two of these residues, Asp190 and Asp256, are present in the amino acid sequences of all polymerases so far studied and are also spatially similar in the four polymerases--the Klenow fragment of Escherichia coli DNA polymerase I, HIV-1 reverse transcriptase, T7 RNA polymerase, and rat DNA pol beta--whose crystal structures are now known. A two-metal ion mechanism is described for the nucleotidyl transfer reaction and may apply to all polymerases. In the ternary complex structures analyzed, pol beta binds to the DNA template-primer in a different manner from that recently proposed for other polymerase-DNA models.

Animals↗
PubMed2004

Differential effects of habitat complexity, predators and competitors on abundance of juvenile and adult coral reef fishes.

Greater structural complexity is often associated with greater abundance and diversity, perhaps because high complexity habitats reduce predation and competition. Using 16 spatially isolated live-coral reefs in the Bahamas, I examined how abundance of juvenile (recruit) and adult (non-recruit) fishes was affected by two factors: (1) structural habitat complexity and (2) the presence of predators and interference competitors. Manipulating the abundance of low and high complexity corals created two levels of habitat complexity, which was cross-factored with the presence or absence of resident predators (sea basses and moray eels) plus interference competitors (territorial damselfishes). Over 60 days, predators and competitors greatly reduced recruit abundance regardless of habitat complexity, but did not affect adult abundance. In contrast, increased habitat complexity had a strong positive effect on adult abundance and a weak positive effect on recruit abundance. Differential responses of recruits and adults may be related to the differential effects of habitat complexity on their primary predators. Sedentary recruits are likely most preyed upon by small resident predators that ambush prey, while larger adult fishes that forage widely and use reefs primarily for shelter are likely most preyed upon by large transient predators that chase prey. Increased habitat complexity may have inhibited foraging by transient predators but not resident predators. Results demonstrate the importance of habitat complexity to community dynamics, which is of concern given the accelerated degradation of habitats worldwide.

Analysis of Variance↗
PubMed2005

A quantitative analysis of interfacial amino acid conservation in protein-protein hetero complexes.

A long-standing question in molecular biology is whether interfaces of protein-protein complexes are more conserved than the rest of the protein surfaces. Although it has been reported that conservation can be used as an indicator for predicting interaction sites on proteins, there are recent reports stating that the interface regions are only slightly more conserved than the rest of the protein surfaces, with conservation signals not being statistically significant enough for predicting protein-protein binding sites. In order to properly address these controversial reports we have studied a set of 28 well resolved hetero complex structures of proteins that consists of transient and non-transient complexes. The surface positions were classified into four conservation classes and the conservation index of the surface positions was quantitatively analyzed. The results indicate that the surface density of highly conserved positions is significantly higher in the protein-protein interface regions compared with the other regions of the protein surface. However, the average conservation index of the patches in the interface region is not significantly higher compared with other surface regions of the protein structures. This finding demonstrates that the number of conserved residue positions is a more appropriate indicator for predicting protein-protein binding sites than the average conservation index in the interacting region. We have further validated our findings on a set of 59 benchmark complex structures. Furthermore, an analysis of 19 complexes of antigen-antibody interactions shows that there is no conservation of amino acid positions in the interacting regions of these complexes, as expected, with the variable region of the immunoglobulins interacting mostly with the antigens. Interestingly, antigen interacting regions also have a higher number of non-conserved residue positions in the interacting region than the rest of the protein surface.

Amino Acid Sequence↗
PubMed1996

Structural and Kinetic Studies of Spin Crossover in an Iron(II) Complex with a Novel Tripodal Ligand.

Configurational and ligand conformational influences on the kinetics of (1)A(1) right harpoon over left harpoon (5)T(2) spin crossover in the Fe(II) complex with the novel tripodal ligand, 1,1,1-tris((N-(2-pyridylmethyl)-N-methylamino)methyl)ethane (tptMetame), have been explored. Despite having six chelate rings and three chiral nitrogen atoms, only one enantiomeric pair of isomers, Delta, SSS, and Lambda, RRR, of the complex ion is observed. The conformation of the three rings forming the upper "cap" of the complex structure can be assigned delta or lambda with respect to the 3-fold molecular axis. X-ray data at 300 and 153 K, above and below the critical temperature for the spin transition, show that the conformation of the ligand "cap" is the same as the absolute configuration of the complex, with the same Lambdalambda(CAP)(or Deltadelta(CAP)) combination prevailing for both the LS ((1)A(1)) and HS ((5)T(2)) isomers. Molecular mechanics calculations further show that the ligand energy remains lowest for this Lambdalambda(CAP) (or Deltadelta(CAP)) combination at all Fe-N distances over the range spanning the LS and HS isomers. Measurements of the spin crossover relaxation time have been carried out in solution over the temperature range 293-170 K. The observed monophasic relaxation traces are also consistent with the absolute configuration of the complex remaining unaltered during the spin crossover.

Journal Article↗
PubMed2004

Mono-, di- and trinuclear 2,3,5,6-tetrakis(2-pyridyl)pyrazine (tppz)-containing copper(II) complexes: syntheses, crystal structures and magnetic properties.

Three new copper(ii) complexes of formula [Cu(tppz)(NCO)(2)].0.4H(2)O (1), [Cu(2)(tppz)Br(4)](2) and [Cu(3)(tppz)(C(5)O(5))(3)(H(2)O)(3)].7H(2)O (3)[tppz = 2,3,5,6-tetrakis(2-pyridyl)pyrazine; C(5)O(5)(2-) = croconate, dianion of 4,5-dihydroxycyclopent-4-ene-1,2,3-trione] have been synthesised and structurally characterized by X-ray diffraction methods. The structure of complex is made up of neutral [Cu(tppz)(NCO)(2)] mononuclear units and uncoordinated water molecules. The mononuclear units are grouped by pairs to give a rather short copper-copper distance of 3.9244(4) angstroms. The structure of complex 1 consists of neutral tppz-bridged [Cu(2)(tppz)Br(4)] dinuclear units, the copper-copper separation across tppz being 6.6198(1) angstroms. The dinuclear units are further connected through weak, double out-of-plane Cu-Br...Cu bridges [Br(1)...Cu(1a) 4.0028(17) angstroms] creating tetranuclear entities, the copper-copper separation through this interaction being 4.3299(21) angstroms. The structure of complex 3 is built of neutral [Cu(3)(tppz)(C(5)O(5))(3)(H(2)O)(3)] trinuclear units and uncoordinated water molecules. Tppz and one of the croconate groups act as bridging ligands, the former exhibiting the bis-terdentate coordination mode and the latter adopting an unusual asymmetrical bis-bidentate bridging mode through three adjacent oxygen atoms. The other two croconate groups exhibit the bidentate coordination mode. The intramolecular copper-copper separations are 6.5417(9)(across tppz) and 4.3234(9) angstroms (through bis-bidentate croconato). The magnetic properties of 2 and 3 have been investigated in the temperature range 1.9-300 K. The magnetic behaviour of complex 2 is that of an antiferromagnetically coupled copper(II) dimer (J = -40.9 cm(-1), the Hamiltonian being H = -JS(A).S(B)). In the case of compound , the chi(M) T vs. T plot is typical of an overall antiferromagnetic coupling with a low-lying spin doublet being fully populated at T < 10 K. The values of the intramolecular antiferromagnetic interactions in 3 are -19.9 (across tppz) and -32.9 cm(-1)(through bridging croconato). Density functional type calculations were performed on model dinuclear fragments of 3 in order to analyze the efficiency of the exchange pathways involved and also to substantiate the coupling parameters.

Journal Article↗
PubMed1975

The fine structure and phosphatase cytochemistry of the golgi complex and associated structures in the sertoli cells of Syrian hamsters.

The Golgi complex in the Sertoli cell of the Syrian hamster is well developed and consists of stacks of cisternae and associated vesicles. The inner- and outermost cisternae of the Golgi stacks are usually moderately dilated and exhibit numerous fenestrations. The middle portions of the intermediate cisternae are greatly flattened and not fenestrated, but toward the periphery these cisternae gradually become dilated and show a few fenestrations. On the inner aspect of the Golgi stacks the following structures are seen frequently: (1) one or two series of linearly arrayed circular profiles some of which are interconnected by tubules; (2) networks of anastomosing tubules with circular or oval meshes (800 to 1200 A in diameter); and/or (3) irregularly disposed tubules. The circular profiles and tubules are approximately 450 A in diameter. Acid phosphatase activity was localized in these anastomosing tubules when the tissues were incubated for more than one hour in a modified Gomori's medium (Barka and Anderson, 1963). Strong thiamine pyrophosphatase activity was demonstrated in the inner one to three cisternae of the Golgi stacks but not in the associated tubules. The system of the Golgi associated tubules is morphologically and histochemically distinct from the Golgi stacks and is probably equivalent to the Golgi-endoplasmic reticulum-lysosome system (GERL) in other cell types. The three dimensional aspects of the GERL-equivalent system are discussed.

Acid Phosphatase↗
PubMed2005

Crystal structures and magnetic properties of complexes of M(II)Cl2 (M = Cu, Ni, and Co) coordinated with 4-(N-tert-butyloxyamino)-2-(methoxymethylenyl)pyridine: 2D magnetic anisotropy of the aminoxyl-Co(II) complex in the crystalline state.

Three metal complexes, [M(II)Cl2(4NOPy-OMe)2] (M = Cu (1), Ni (2), and Co (3)), were prepared by mixing the corresponding metal chloride and 4-(N-tert-butyloxyamino)-2-(methoxymethylenyl)pyridine, 4NOPy-OMe, in 1:2 ratio. Complex 1 has two structures (complexes A and B) with similar coordination geometries, compressed octahedrons. In the crystal structure, complexes A and B locate alternately in short distances (C(radical)...C(beta) = 3.17 and 3.23 A) to form a 1-D chain structure. Complexes 2 and 3 are isomorphous and have a slightly distorted octahedral structure. In the crystal structure, both complexes have intermolecular short contacts (C(radical)...C(alpha) = 3.46 and 3.52 A for 2 and 3, respectively) to form the 2-D structures. The temperature dependence of the chi(mol)T values for the three complexes indicated that the magnetic interactions between the radicals and the metal ions within the complexes were ferromagnetic. By fitting a modified Fisher 1-D model to the data of the chi(mol)T vs T plot for 1, we estimated the intra- and intermolecular (intrachain) exchange coupling constants to be J1/kB = 60.2 and J2/kB = -7.02 K, respectively. On the other hand, complexes 2 and 3 showed steep increases of the chi(mol)T value below ca. 3 K, indicating that the long-range magnetic ordering is operating. The 1/chi(mol) vs T plot for 2 was analyzed by a Curie-Weiss model to give theta = 6.25 K and C = 2.02 cm3 K mol(-1) with g(Ni) = 2.25. Complex 3 was investigated in more detail using an orientated sample. Magnetic behavior strongly depends on the direction of the applied field, in which the c axis perpendicular to the ab plane is an easy axis for magnetization. Direct current (dc) and alternating current (ac) magnetic susceptibility measurements revealed that complex 3 had a magnetic phase transition of T(c) = 2.14 K and exhibited a glasslike magnetic behavior below T(c).

Cobalt↗
PubMed1996

Mechanistic implication of crystal structures of the cyclophilin-dipeptide complexes.

The structures of cyclophilin A complexed with dipeptides of Ser-Pro, His-Pro, and Gly-Pro have been determined and refined at high resolution. Comparison of these structures revealed that the dipeptide complexes have the same molecular conformation and the same binding of the dipeptides. The side chains of the N-terminal amino acid of the above dipeptides do not strongly interact with cyclophilin, implying their minor contribution to the cis-trans isomerization and thus accounting for the broad catalytic specificity of the enzyme. The binding of the dipeptides is similar to that of the common substrate succinyl-Ala-Ala-Pro-Phe-p-nitroanilide in terms of the N-terminal hydrogen bonding and the hydrophobic interaction of the proline side chain. However, substantial difference between these structures are observed in (1) hydrogen bonding between the carboxyl terminus of the peptides and Arg55 and between Arg55 and Gln63, (2) the side chain conformation of Arg55, and (3) water binding at the active site. These differences imply either that dipeptides are not substrates but competitive inhibitors of peptidyl-prolyl cis-trans isomerases or that dipeptides are subject to different catalytic mechanisms from tetrapeptides.

Amino Acid Isomerases↗
PubMed1999

Comparison of the cytochrome bc1 complex with the anticipated structure of the cytochrome b6f complex: Le plus ça change le plus c'est la même chose.

Structural alignment of the integral cytochrome b6-SU IV subunits with the solved structure of the mitochondrial bc1 complex shows a pronounced asymmetry. There is a much higher homology on the p-side of the membrane, suggesting a similarity in the mechanisms of intramembrane and interfacial electron and proton transfer on the p-side, but not necessarily on the n-side. Structural differences between the bc1 and b6f complexes appear to be larger the farther the domain or subunit is removed from the membrane core, with extreme differences between cytochromes c1 and f. A special role for the dimer may involve electron sharing between the two hemes b(p), which is indicated as a probable event by calculations of relative rate constants for intramonomer heme b(p) --> heme b(n), or intermonomer heme b(p) --> heme b(p) electron transfer. The long-standing observation of flash-induced oxidation of only approximately 0.5 of the chemical content of cyt f may be partly a consequence of the statistical population of ISP bound to cytfon the dimer. It is proposed that the p-side domain of cyt f is positioned with its long axis parallel to the membrane surface in order to: (i) allow its large and small domains to carry out the functions of cyt c1 and suVIII, respectively, of the bc1 complex, and (ii) provide maximum dielectric continuity with the membrane. (iii) This position would also allow the internal water chain ("proton wire") of cyt f to serve as the p-side exit port for an intramembrane H+ transfer chain that would deprotonate the semiquinol located in the myxothiazol/MOA-stilbene pocket near heme b(p). A hypothesis is presented for the identity of the amino acid residues in this chain.

Animals↗
PubMed2003

Catalytic mechanism of the inverting N-acetylglucosaminyltransferase I: DFT quantum mechanical model of the reaction pathway and determination of the transition state structure.

The complex N-glycan structures on glycoproteins play important roles in cell adhesion and recognition events in metazoan organisms. A critical step in the biosynthetic pathway leading from high mannose to these complex structures includes the transfer of N-acetylglucosamine (GlcNAc) to a mannose residue by the inverting N-acetylglucosaminyltransferase I (GnT-I). The catalytic mechanism of this enzymatic reaction is explored herein using DFT quantum chemical methods. The computational model used to follow the reaction is based on the X-ray crystallographic structure of GnT-I and contains 127 atoms that represent fragments of residues critical for the substrate binding and catalysis. The mechanism of the catalytic reaction was monitored by means of a 2D potential energy map calculated as a function of predefined reaction coordinates at the B3LYP/6-31G** level. This potential energy surface revealed one transition state associated with a reaction pathway following a concerted mechanism. The reaction barrier was estimated, and the structure of the transition state was characterized at the B3LYP/6-311++G**// B3LYP/6-31G** level.

Binding Sites↗
PubMed2005

Physicochemical and residue conservation calculations to improve the ranking of protein-protein docking solutions.

Many protein-protein docking algorithms generate numerous possible complex structures with only a few of them resembling the native structure. The major challenge is choosing the near-native structures from the generated set. Recently it has been observed that the density of conserved residue positions is higher at the interface regions of interacting protein surfaces, except for antibody-antigen complexes, where a very low number of conserved positions is observed at the interface regions. In the present study we have used this observation to identify putative interacting regions on the surface of interacting partners. We studied 59 protein complexes, used previously as a benchmark data set for docking investigations. We computed conservation indices of residue positions on the surfaces of interacting proteins using available homologous sequences and used this information to filter out from 56% to 86% of generated docked models, retaining near-native structures for further evaluation. We used a reverse filter of conservation score to filter out the majority of nonnative antigen-antibody complex structures. For each docked model in the filtered subsets, we relaxed the conformation of the side chains by minimizing the energy with CHARMM, and then calculated the binding free energy using a generalized Born method and solvent-accessible surface area calculations. Using the free energy along with conservation information and other descriptors used in the literature for ranking docking solutions, such as shape complementarity and pair potentials, we developed a global ranking procedure that significantly improves the docking results by giving top ranks to near-native complex structures.

Algorithms↗
PubMed1996

Conformation, protein-carbohydrate interactions and a novel subunit association in the refined structure of peanut lectin-lactose complex.

The structure of the complex of the tetrameric peanut lectin with lactose has been refined to an R-value of 16.4% using 2.25 angstroms resolution X-ray diffraction data. The subunit conformation in the structure is similar to that in other legume lectins except in the loops. It has been shown that in the tertiary structure of legume lectins, the short five-stranded sheet plays a major role in connecting the larger flat six-stranded and curved seven-stranded sheets. Furthermore, the loops that connect the strands at the two ends of the seven-stranded sheet curve toward and interact with each other to produce a second hydrophobic core in addition to the one between the two large sheets. The protein-lactose interactions involve the invariant features observed in other legume lectins in addition to those characteristic of peanut lectin. The "open" quaternary association in peanut lectin is stabilised by hydrophobic, hydrogen-bonded and water-mediated interactions. Contrary to the earlier belief, the structure of peanut lectin demonstrates that the variability in quaternary association in legume lectins, despite all of them having nearly the same tertiary structure, is not necessarily caused by covalently bound carbohydrate. An attempt has been made to provide a structural rationale for this variability, on the basis of buried surface areas during dimerisation. A total of 45 water molecules remain invariant when the hydration shells of the four subunits are compared. A majority of them appear to be involved in stabilising loops.

Carbohydrate Metabolism↗
PubMed2005

Vanadium(III) and vanadium(V) amine tris(phenolate) complexes.

The coordination chemistry of amine tris(phenolate) ligands around V(III) and V(V) is described for the first time. Three amine tris(phenolate) ligands were employed featuring different steric and electronic influence exerted by the phenolate substituents in the ortho and para positions being either t-Bu, Me, or Cl. V(III) complexes of all ligands (1-3) were readily obtained by reaction between the ligand precursors and VCl3(THF)3 in the presence of triethylamine. The complexes obtained were pentacoordinate, a THF ligand completing the coordination sphere of the metal, which was found to be of almost perfect TBP geometry, as revealed by crystallography. V(V) oxo complexes of all the ligands (4-6) were readily obtained by a reaction between the ligand precursors and VO(OPr)3. The oxo complexes of the alkyl-bearing ligands (4 and 5) could also be synthesized by the air oxidation of the corresponding V(III) complexes (1 and 2); however, the attempted air oxidation of the V(III) complex bound to the electron-poor ligand (3) did not yield the corresponding oxo complex 6. 1H NMR and crystallographic analysis of complexes 4 and 5 supported their TBP structures. Complex 6, on the other hand, was found to be composed of a TBP complex (6a) and an octahedral complex (6b) in equilibrium, the octahedral complex being more stable at lower temperatures. An X-ray structure of 6b revealed a mononuclear oxo complex, the sixth coordination site being occupied by an aqua ligand to which two THF molecules are H-bonded. Complexes 4-6 catalyze the epoxidation of olefins by t-BuOOH, albeit slowly. These complexes may thus be considered as structural and functional models of vanadium-dependent haloperoxidase enzymes.

Journal Article↗
PubMed2003

The structure of JNK3 in complex with small molecule inhibitors: structural basis for potency and selectivity.

The c-Jun terminal kinases (JNKs) are members of the mitogen-activated protein (MAP) kinase family and regulate signal transduction in response to environmental stress. Activation of JNK3, a neuronal-specific isoform, has been associated with neurological damage, and as such, JNK3 may represent an attractive target for the treatment of neurological disorders. The MAP kinases share between 50% and 80% sequence identity. In order to obtain efficacious and safe compounds, it is necessary to address the issues of potency and selectivity. We report here four crystal structures of JNK3 in complex with three different classes of inhibitors. These structures provide a clear picture of the interactions that each class of compound made with the kinase. Knowledge of the atomic interactions involved in these diverse binding modes provides a platform for structure-guided modification of these compounds, or the de novo design of novel inhibitors that could satisfy the need for potency and selectivity.

Adenosine Triphosphate↗