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PubMed2004

SNP analysis combined with protein structure prediction defines structure-functional relationships in cancer related cytochrome P450 estrogen metabolism.

The P450 family of proteins has more than 1000 representatives, which despite sometimes relatively low sequence identity have a surprisingly high level of structural similarity. This fact makes this family of proteins ideal candidate for various types of modeling based on protein structure prediction. A number of P450 proteins, including CYPs 1A1, 1A2, 1B1, 3A4, 11B2, 17, and 19, play a role in the metabolism of estrogen. Inhibitors of these proteins could be very promising drugs for hormonal treatment of postmenopausal breast cancer. Population studies have yielded a significant amount of data describing the relationship between single nucleotide polymorphisms (SNP) in DNA and cancer risk related to these proteins. A combination of SNP analysis with protein structure prediction can be a very useful strategy in investigations of structure-functional relations of P450 proteins and structure-based drug design. Here we will demonstrate how protein structure prediction combined with genetic SNP analysis can be useful for potential drug design and possibly, individual treatment of breast cancer.

Amino Acid Sequence↗
PubMed1992

Alternative structures for alternating poly(dA-dT) tracts: the structure of the B-DNA decamer C-G-A-T-A-T-A-T-C-G.

The X-ray crystal structure of the decamer C-G-A-T-A-T-A-T-C-G has been solved with two contrasting cations, Ca2+ and Mg2+. Crystals with calcium are space group P2(1)2(1)2(1), cell dimensions a = 38.76 A, b = 40.06 A, and c = 33.73 A, and diffract to 1.7-A resolution. Crystals with magnesium have the same space group, cell dimensions a = 38.69 A, b = 39.56 A, and c = 33.64 A, and diffract to 2.0 A. Their structures were solved independently by molecular replacement, beginning with idealized Arnott B-DNA geometry. The calcium structure refined to R = 17.8% for the 3683 reflections greater than 2 sigma, with 404 DNA atoms, 95 solvent peaks, and 1 Ca(H2O)7(2+) ion. The magnesium structure refined to R = 16.5% for the 1852 reflections greater than 2 sigma, with 404 DNA atoms, 62 solvent peaks, and 1 Mg(H2O)6(2+) ion. The two structures are virtually identical and are isostructural with C-G-A-T-C-G-A-T-C-G [Grzeskowiak et al. (1991) J. Biol. Chem. 266, 8861-8883] and C-G-A-T-T-A-A-T-C-G [Quintana et al. (1992) J. Mol. Biol. 225, 375-395]. Comparison of C-G-A-T-A-T-A-T-C-G with C-G-C-A-T-A-T-A-T-G-C-G [Yoon et al. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 6332-6336] shows that the expected alternation of twist angles is found in the central A-T-A-T-A-T region of the decamer (A-T small, T-A large), but the minor groove remains wide at the center, rather than narrow. Minor groove narrowing is produced, in these two structures, not by overwinding of the helix, but by an increase in base pair propeller. This analysis confirms the concept that poly(dA-dT).poly(dA-dT) is polymorphous, with different local conformations possible in different local environments.

Base Sequence↗
PubMed1997

Hierarchical protein structure superposition using both secondary structure and atomic representations.

The structural comparison of proteins has become increasingly important as a means to identify protein motifs and fold families. In this paper we present a new algorithm for the comparison of proteins based on a hierarchy of structural representations, from the secondary structure level to the atomic level. Our technique represents alpha-helices and beta-strands as vectors and uses a set of seven scoring functions to compare pairs of vectors from different proteins. The scores obtained are used in a dynamic programming algorithm that finds the best local alignment of the two sets of vectors. The second step in our algorithm is based on the atomic coordinates of the protein structures and improves the initial vector alignment by iteratively minimizing the RMSD between pairs of nearest atoms from the two proteins. We refine the final alignment by determining a core of well aligned atoms and minimizing the RMSD of this core. In a comparison of our method to Holm and Sander's DALI algorithm, our program was able to detect structural similarity at the same level as DALI. We also performed searches of a representative set of the Protein Data Bank (PDB) using our program and detected structurally similarity between several distantly related proteins.

Algorithms↗
PubMed2004

A simple topological representation of protein structure: implications for new, fast, and robust structural classification.

A topological representation of proteins is developed that makes use of two metrics: the Euclidean metric for identifying natural nearest neighboring residues via the Delaunay tessellation in Cartesian space and the distance between residues in sequence space. Using this representation, we introduce a quantitative and computationally inexpensive method for the comparison of protein structural topology. The method ultimately results in a numerical score quantifying the distance between proteins in a heuristically defined topological space. The properties of this scoring scheme are investigated and correlated with the standard Calpha distance root-mean-square deviation measure of protein similarity calculated by rigid body structural alignment. The topological comparison method is shown to have a characteristic dependence on protein conformational differences and secondary structure. This distinctive behavior is also observed in the comparison of proteins within families of structural relatives. The ability of the comparison method to successfully classify proteins into classes, superfamilies, folds, and families that are consistent with standard classification methods, both automated and human-driven, is demonstrated. Furthermore, it is shown that the scoring method allows for a fine-grained classification on the family, protein, and species level that agrees very well with currently established phylogenetic hierarchies. This fine classification is achieved without requiring visual inspection of proteins, sequence analysis, or the use of structural superimposition methods. Implications of the method for a fast, automated, topological hierarchical classification of proteins are discussed.

Amino Acid Sequence↗
PubMed2001

Structure of c-phycocyanin from the thermophilic cyanobacterium Synechococcus vulcanus at 2.5 A: structural implications for thermal stability in phycobilisome assembly.

The crystal structure of the light-harvesting phycobiliprotein, c-phycocyanin from the thermophilic cyanobacterium Synechochoccus vulcanus has been determined by molecular replacement to 2.5 A resolution. The crystal belongs to space group R32 with cell parameters a=b=188.43 A, c=61.28 A, alpha=beta=90 degrees, gamma=120 degrees, with one (alphabeta) monomer in the asymmetric unit. The structure has been refined to a crystallographic R factor of 20.2 % (R-free factor is 24.4 %), for all data to 2.5 A. The crystals were grown from phycocyanin (alphabeta)(3) trimers that form (alphabeta)(6) hexamers in the crystals, in a fashion similar to other phycocyanins. Comparison of the primary, tertiary and quaternary structures of the S. vulcanus phycocyanin structure with phycocyanins from both the mesophilic Fremyella diplsiphon and the thermophilic Mastigocladus laminosus were performed. We show that each level of assembly of oligomeric phycocyanin, which leads to the formation of the phycobilisome structure, can be stabilized in thermophilic organisms by amino acid residue substitutions. Each substitution can form additional ionic interactions at critical positions of each association interface. In addition, a significant shift in the position of ring D of the B155 phycocyanobilin cofactor in the S. vulcanus phycocyanin, enables the formation of important polar interactions at both the (alphabeta) monomer and (alphabeta)(6) hexamer association interfaces.

Algal Proteins↗
PubMed2005

Structure of the connector of bacteriophage T7 at 8A resolution: structural homologies of a basic component of a DNA translocating machinery.

The three-dimensional structure of the bacteriophage T7 head-to-tail connector has been obtained at 8A resolution using cryo-electron microscopy and single-particle analysis from purified recombinant connectors. The general morphology of the T7 connector is that of a 12-folded toroidal homopolymer with a channel that runs along the longitudinal axis of the particle. The structure of the T7 connector reveals many structural similarities with the connectors from other bacteriophages. Docking of the atomic structure of the varphi29 connector into the three-dimensional reconstruction of T7 connector reveals that the narrow, distal region of the two oligomers are almost identical. This region of the varphi29 connector has been suggested to be involved in DNA translocation, and is composed of an alpha-beta-alpha-beta-beta-alpha motif. A search for alpha-helices in the same region of the T7 three-dimensional map has located three alpha-helices in approximately the same position as those of the varphi29 connector. A comparison of the predicted secondary structure of several bacteriophage connectors, including among others T7, varphi29, P22 and SPP1, reveals that, despite the lack of sequence homology, they seem to contain the same alpha-beta-alpha-beta-beta-alpha motif as that present in the varphi29 connector. These results allow us to suggest a common architecture related to a basic component of the DNA translocating machinery for several viruses.

Bacteriophage T7↗
PubMed2002

Solution structure of the DFF-C domain of DFF45/ICAD. A structural basis for the regulation of apoptotic DNA fragmentation.

DFF45/ICAD has dual functions in the final stage of apoptosis, by acting as both a folding chaperone and a DNase inhibitor of DFF40/CAD. Here, we present the solution structure of the C-terminal domain of DFF45, which is essential for its chaperone-like activity. The structure of this domain (DFF-C) consists of four alpha helices, which are folded in a novel helix-packing arrangement. The 3D structure reveals a large cluster of negatively charged residues on the molecular surface of DFF-C. This observation suggests that charge complementation plays an important role in the interaction of DFF-C with the positively charged catalytic domain of DFF40, and thus for the chaperone activity of DFF45. The structure of DFF-C also provides a rationale for the loss of the chaperone activity in DFF35, a short isoform of DFF45. Indeed, in DFF35, the amino acid sequence is truncated in the middle of the second alpha helix constituting the structure of DFF-C, and thus both the hydrophobic core and the cluster of negative charges are disrupted.

Amino Acid Sequence↗
PubMed2001

Structural basis for a change in substrate specificity: crystal structure of S113E isocitrate dehydrogenase in a complex with isopropylmalate, Mg2+, and NADP.

Isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate and has negligible activity toward other (R)-malate-type substrates. The S113E mutant of IDH significantly improves its ability to utilize isopropylmalate as a substrate and switches the substrate specificity (k(cat)/K(M)) from isocitrate to isopropylmalate. To understand the structural basis for this switch in substrate specificity, we have determined the crystal structure of IDH S113E in a complex with isopropylmalate, NADP, and Mg(2+) to 2.0 A resolution. On the basis of a comparison with previously determined structures, we identify distinct changes caused by the amino acid substitution and by the binding of substrates. The S113E complex exhibits alterations in global and active site conformations compared with other IDH structures that include loop and helix conformational changes near the active site. In addition, the angle of the hinge that relates the two domains was altered in this structure, which suggests that the S113E substitution and the binding of substrates act together to promote catalysis of isopropylmalate. Ligand binding results in reorientation of the active site helix that contains residues 113 through 116. E113 exhibits new interactions, including van der Waals contacts with the isopropyl group of isopropylmalate and a hydrogen bond with N115, which in turn forms a hydrogen bond with NADP. In addition, the loop and helix regions that bind NADP are altered, as is the loop that connects the NADP binding region to the active site helix, changing the relationship between substrates and enzyme. In combination, these interactions appear to provide the basis for the switch in substrate specificity.

Amino Acid Substitution↗
PubMed2006

Structure-based drug design and structural biology study of novel nonpeptide inhibitors of severe acute respiratory syndrome coronavirus main protease.

Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M(pro)), a protein required for the maturation of SARS-CoV, is vital for its life cycle, making it an attractive target for structure-based drug design of anti-SARS drugs. The structure-based virtual screening of a chemical database containing 58,855 compounds followed by the testing of potential compounds for SARS-CoV M(pro) inhibition leads to two hit compounds. The core structures of these two hits, defined by the docking study, are used for further analogue search. Twenty-one analogues derived from these two hits exhibited IC50 values below 50 microM, with the most potent one showing 0.3 microM. Furthermore, the complex structures of two potent inhibitors with SARS-CoV M(pro) were solved by X-ray crystallography. They bind to the protein in a distinct manner compared to all published SARS-CoV M(pro) complex structures. They inhibit SARS-CoV M(pro) activity via intensive H-bond network and hydrophobic interactions, without the formation of a covalent bond. Interestingly, the most potent inhibitor induces protein conformational changes, and the inhibition mechanisms, particularly the disruption of catalytic dyad (His41 and Cys145), are elaborated.

Binding Sites↗
PubMed1996

Molecular structure, conformational analysis, and structure-activity studies of Dendrotoxin and its homologues using molecular mechanics and molecular dynamics techniques.

Three-dimensional structures of Dendrotoxin (DtX), Toxin-I (DpI), and Toxin-K (DpK) were determined using molecular mechanics and molecular dynamics techniques. The overall molecular conformation and protein folding of the three dendrotoxins are very similar to the published crystal structures of bovine pancreatic trypsin inhibitor (BPTI) and alpha-DtX. Major secondary structural regions of the dendrotoxins are stable without much fluctuation during the dynamics simulation; the regions corresponding to the turns and bends (rich in lysines and arginines) exhibit more fluctuations. The conformational angles and the C alpha...C alpha' distances of the three disulfides (in each of the dendrotoxins) are different from each other. Comparative model building studies, involving the dendrotoxins and the proteinases, reveal that the key interactions (observed in BPTI-trypsin complex) needed for anti-protease activity are absent due to structural differences between the dendrotoxins and BPTI at the anti-protease loop; this explains the inability of the dendrotoxins to inhibit proteinases. The model also suggests that the solvent-exposed beta-turn region, rich in lysines (residues 26-28), might bind directly to the extracellular anionic sites of the receptors (K+ channels) by ionic interactions. The strikingly homologous cysteine distribution (Cys-x-x-x-Cys) in DtX, DpI, and DpK, at the C-terminus, induces the occurrence of a characteristic conformational motif, consisting of an alpha-helix (in an amphiphilic environment) stabilized by two disulfides, one involving a cysteine at the beta-strand, and the other at the N-terminus. This amphiphilic secondary structural element seems to provide the rigid frame work needed for exposing the proposed active site region of the dendrotoxins to the anionic sites of the K+ channel receptors.

Amino Acid Sequence↗
PubMed1999

Secondary structures and structural fluctuation in a dimeric protein, Streptomyces subtilisin inhibitor.

Based on the nuclear magnetic resonance assignments of a dimeric protein, Streptomyces subtilisin inhibitor (SSI), microscopic details of secondary structures in solution have been elucidated. The chemical shift index of C(alpha) signals, together with information on the hydrogen exchange rates of the backbone amide protons, were used to identify secondary structures. The locations of these secondary structures were found to be different in some critical points from those determined earlier by X-ray crystallography of the crystal. Notably, the beta3 strand is completely missing and the alpha2 helix is extended toward the C-terminus. Furthermore, hydrogen exchange experiments of individual peptide NH protons under strongly folding conditions revealed mechanisms of global and local structural fluctuation within the dimeric structure. It has been suggested that the global fluctuation of the monomeric unit occurs without affecting the accompanying monomer, in contrast to the equilibrium thermal unfolding, which is cooperative. Higher protection against hydrogen exchange for residues in part of the beta4 strand implies that this region might serve as a folding core.

Amino Acid Sequence↗