Biomedical subjects

Xianfeng Gu

Publications and source records attributed to Xianfeng Gu.

9 recordsLinked to original sources

PubMed2006

Design and evaluation of hydroxamate derivatives as metal-mediated inhibitors of a protein tyrosine kinase.

Protein tyrosine kinases use two Mg(2+) ions as cofactors in catalysis, one as the ATP-Mg complex (M1) and the other as an essential activator (M2). The M2-binding site has high affinity for transition metal cations such as cobalt and zinc. Taking advantage of this high affinity, we examined hydroxamates as metal-mediated inhibitors against C-terminal Src kinase (Csk), a protein tyrosine kinase. Of a small group of amino acid hydroxamates, tyrosine and phenylalanine hydroxamates inhibited Csk activity only in the presence of Co(2+). Four classes of phenylalanine and tyrosine hydroxamate derivatives were synthesized and evaluated as metal-mediated inhibitors of Csk, leading to improved inhibition and a better understanding of the structure-activity relationships. This study suggests that hydroxamates may serve as a general scaffold for developing metal-mediated inhibitors against protein tyrosine kinases. To the best of our knowledge, this is the first report of designing metal-mediated inhibitors against a protein tyrosine kinase by targeting a metal binding site.

Cations, Divalent↗

PubMed2006

Conformational basis for SH2-Tyr(P)527 binding in Src inactivation.

Src protein-tyrosine kinase contains a myristoylation motif, a unique region, an Src homology (SH) 3 domain, an SH2 domain, a catalytic domain, and a C-terminal tail. The C-terminal tail contains a Tyr residue, Tyr527. Phosphorylation of Tyr527 triggers Src inactivation, caused by Tyr(P)527 binding to the SH2 domain. In this study, we demonstrated that a conformational contribution, not affinity, is the predominant force for the intramolecular SH2-Tyr(P)527 binding, and we characterized the structural basis for this conformational contribution. First, a phosphopeptide mimicking the C-terminal tail is an 80-fold weaker ligand than the optimal phosphopeptide, pYEEI, and similar to a phosphopeptide containing three Ala residues following Tyr(P) in binding to the Src SH2 domain. Second, the SH2-Tyr(P)527 binding is largely independent of the amino acid sequence surrounding Tyr(P)527, and only slightly decreased by an inactivating mutation in the SH2 domain. Furthermore, even the unphosphorylated C-terminal tail with the sequence of YEEI suppresses Src activity by binding to the SH2 domain. These experiments demonstrate that very weak affinity is sufficient for the SH2-Tyr(P)527 binding in Src inactivation. Third, the effective intramolecular SH2-Tyr(P)527 binding is attributed to a conformational contribution that requires residues Trp260 and Leu255. Although the SH3 domain is essential for Src inactivation by Tyr(P)527, it does not contribute to the SH2-Tyr(P)527 binding. These findings suggest a conformation-based Src inactivation model, which provides a unifying framework for understanding Src activation by a variety of mechanisms.

Amino Acid Motifs↗

PubMed2005

A minimal structural analogue of cyclic ADP-ribose: synthesis and calcium release activity in mammalian cells.

Cyclic ADP-ribose (cADPR) is an endogenous Ca(2+)-mobilizing second messenger in many cell types and organisms. Although the biological activity of several modified analogues of cADPR has been analyzed, most of these structures were still very similar to the original molecule. Recently, we have introduced simplified analogues in which the northern ribose (N(1)-linked ribose) was replaced by an ether strand. Here we also demonstrate that the southern ribose (N(9)-linked ribose) can be replaced by an ether strand resulting in N(1)-[(phosphoryl-O-ethoxy)-methyl]-N(9)-[(phosphoryl-O-ethoxy)-methyl]-hypoxanthinecyclic pyrophosphate (cIDP-DE). This minimal structural analogue of cyclic ADP-ribose released Ca(2+) from intracellular stores of permeabilized Jurkat T lymphocytes. In intact T lymphocytes initial subcellular Ca(2+) release events, global Ca(2+) release, and subsequent global Ca(2+) entry were observed. Cardiac myocytes freshly prepared from mice responded to cIDP-DE by increased recruitment of localized Ca(2+) signals and by global Ca(2+) waves.

Animals↗

PubMed2005

Brain surface parameterization using Riemann surface structure.

We develop a general approach that uses holomorphic 1-forms to parameterize anatomical surfaces with complex (possibly branching) topology. Rather than evolve the surface geometry to a plane or sphere, we instead use the fact that all orientable surfaces are Riemann surfaces and admit conformal structures, which induce special curvilinear coordinate systems on the surfaces. Based on Riemann surface structure, we can then canonically partition the surface into patches. Each of these patches can be conformally mapped to a parallelogram. The resulting surface subdivision and the parameterizations of the components are intrinsic and stable. To illustrate the technique, we computed conformal structures for several types of anatomical surfaces in MRI scans of the brain, including the cortex, hippocampus, and lateral ventricles. We found that the resulting parameterizations were consistent across subjects, even for branching structures such as the ventricles, which are otherwise difficult to parameterize. Compared with other variational approaches based on surface inflation, our technique works on surfaces with arbitrary complexity while guaranteeing minimal distortion in the parameterization. It also offers a way to explicitly match landmark curves in anatomical surfaces such as the cortex, providing a surface-based framework to compare anatomy statistically and to generate grids on surfaces for PDE-based signal processing.

Algorithms↗

PubMed2004

Synthesis and biological evaluation of novel membrane-permeant cyclic ADP-ribose mimics: N1-[(5''-O-phosphorylethoxy)methyl]-5'-O-phosphorylinosine 5',5''-cyclicpyrophosphate (cIDPRE) and 8-substituted derivatives.

N1-[(5' '-O-Phosphorylethoxy)methyl]-5'-O-phosphorylinosine 5',5''-cyclicpyrophosphate (cIDPRE 2a) and the 8-substituted derivatives 8-bromo-, 8-azido-, 8-amino-, and 8-Cl-cIDPRE (2b-e) were synthesized from N1-[(5''-acetoxyethoxy)methyl]-2',3'-O-isopropylideneinosine (5) in good yields. The pharmacological activities of cIDPRE and the 8-substituted derivatives (2a-e) were analyzed in intact and permeabilized human Jurkat T-lymphocytes. The results indicate that cIDPRE permeates the plasma membrane, releases Ca2+ from an intracellular, cADPR-sensitive Ca2+ store, and subsequently initiates Ca2+ release-activated Ca2+ entry. The Ca(2+)-releasing activity of cIDPRE was confirmed directly in permeabilized cells. Using time-resolved confocal Ca2+ imaging at the single cell level, the development of global Ca2+ signals starting from local small Ca2+ signals evoked by cIDPRE was observed. 8-N3-cIDPRE 2c and 8-NH2-cIDPRE 2d were similarly effective in their agonistic activity as compared to cIDPRE 2a, showing almost indistinguishable concentration-response curves for 2a, 2c, and 2d and very similar kinetics of Ca2+ signaling. In contrast, the halogenated derivatives 8-Br- and 8-Cl-cIDPRE (2b and 2e) did not significantly elevate [Ca2+]i. Therefore, cIDPRE 2a, 8-N3-cIDPRE 2c, and 8-NH2-cIDPRE 2d are novel membrane permeant cADPR mimic and may provide important novel tools to study cADPR-mediated Ca2+ signaling in intact cells.

Adenosine Diphosphate Ribose↗

PubMed2004

Amplification and propagation of pacemaker Ca2+ signals by cyclic ADP-ribose and the type 3 ryanodine receptor in T cells.

Ligation of the T-cell receptor/CD3 complex results in global Ca(2+) signals that are essential for T-cell activation. We have recently reported that these global Ca(2+) signals are preceded by localized pacemaker Ca(2+) signals. Here, we demonstrate for the first time for human T cells that an increase in signal frequency of subcellular pacemaker Ca(2+) signals at sites close to the plasma membrane, in the cytosol and in the nucleus depends on the type 3 ryanodine receptor (RyR) and its modulation by cyclic ADP-ribose. The spatial distribution of D-myo-inositol 1,4,5-trisphosphate receptors and RyRs indicates a concerted action of both of these receptors/Ca(2+) channels in the generation of initial pacemaker signals localized close to the plasma membrane. Inhibition or knockdown of RyRs resulted in significant decreases in (1) the frequency of initial pacemaker signals localized close to the plasma membrane, and (2) the frequency of localized pacemaker Ca(2+) signals in the inner cytosol. Moreover, upon microinjection of cyclic ADP-ribose or upon extracellular addition of its novel membrane-permeant mimic N-1-ethoxymethyl-substituted cyclic inosine diphosphoribose, similarly decreased Ca(2+) signals were observed in both type 3 RyR-knockdown cells and in control cells microinjected with the RyR antagonist Ruthenium Red. Taken together, our results show that, under physiological conditions in human T cells, RyRs play crucial roles in the local amplification and the spatiotemporal development of subcellular Ca(2+) pacemaker signals.

Biological Clocks↗

PubMed2004

Genus zero surface conformal mapping and its application to brain surface mapping.

We developed a general method for global conformal parameterizations based on the structure of the cohomology group of holomorphic one-forms for surfaces with or without boundaries (Gu and Yau, 2002), (Gu and Yau, 2003). For genus zero surfaces, our algorithm can find a unique mapping between any two genus zero manifolds by minimizing the harmonic energy of the map. In this paper, we apply the algorithm to the cortical surface matching problem. We use a mesh structure to represent the brain surface. Further constraints are added to ensure that the conformal map is unique. Empirical tests on magnetic resonance imaging (MRI) data show that the mappings preserve angular relationships, are stable in MRIs acquired at different times, and are robust to differences in data triangulation, and resolution. Compared with other brain surface conformal mapping algorithms, our algorithm is more stable and has good extensibility.

Algorithms↗

PubMed2003

Genus zero surface conformal mapping and its application to brain surface mapping.

It is well known that any genus zero surface can be mapped conformally onto the sphere and any local portion thereof onto a disk. However, it is not trivial to find a general method which finds a conformal mapping between two general genus zero surfaces. We propose a new variational method which can find a unique mapping between any two genus zero manifolds by minimizing the harmonic energy of the map. We demonstrate the feasibility of our algorithm by applying it to the cortical surface matching problem. We use a mesh structure to represent the brain surface. Further constraints are added to ensure that the conformal map is unique. Empirical tests on MRI data show that the mappings preserve angular relationships, are stable in MRIs acquired at different times, and are robust to differences in data triangulation, and resolution. Compared with other brain surface conformal mapping algorithms, our algorithm is more stable and has good extensibility.

Algorithms↗

PubMedDate not supplied

Meshless thin-shell simulation based on global conformal parameterization.

This paper presents a new approach to the physically-based thin-shell simulation of point-sampled geometry via explicit, global conformal point-surface parameterization and meshless dynamics. The point-based global parameterization is founded upon the rigorous mathematics of Riemann surface theory and Hodge theory. The parameterization is globally conformal everywhere except for a minimum number of zero points. Within our parameterization framework, any well-sampled point surface is functionally equivalent to a manifold, enabling popular and powerful surface-based modeling and physically-based simulation tools to be readily adapted for point geometry processing and animation. In addition, we propose a meshless surface computational paradigm in which the partial differential equations (for dynamic physical simulation) can be applied and solved directly over point samples via Moving Least Squares (MLS) shape functions defined on the global parametric domain without explicit connectivity information. The global conformal parameterization provides a common domain to facilitate accurate meshless simulation and efficient discontinuity modeling for complex branching cracks. Through our experiments on thin-shell elastic deformation and fracture simulation, we demonstrate that our integrative method is very natural, and that it has great potential to further broaden the application scope of point-sampled geometry in graphics and relevant fields.

Algorithms↗