A5022115475- Amino Acid Enzymes and Metabolism
- Enzyme Structure and Function
- Cellular transport and secretion
- Protein Structure and Dynamics
- Glycosylation and Glycoproteins Research
- Mitochondrial Function and Pathology
- Microtubule and mitosis dynamics
- Bacterial Genetics and Biotechnology
- Digestive system and related health
- HER2/EGFR in Cancer Research
- Protease and Inhibitor Mechanisms
- Blood Coagulation and Thrombosis Mechanisms
- Bacillus and Francisella bacterial research
- Liver Disease Diagnosis and Treatment
- Erythrocyte Function and Pathophysiology
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Biochemical and Structural Characterization
- Enzyme Production and Characterization
- Cell Adhesion Molecules Research
- Crystal structures of chemical compounds
- RNA and protein synthesis mechanisms
- Crystallography and molecular interactions
- PARP inhibition in cancer therapy
- Vitamin K Research Studies
University of Oklahoma Health Sciences Center
2012-2022
Oklahoma Medical Research Foundation
2004-2016
University of Kansas
2001-2006
Argonne National Laboratory
2003
Oklahoma State University
2001-2002
Institute of Crystallography
2002
Institut de Biologia Molecular de Barcelona
2000-2001
Centro de Investigación y Desarrollo
2000-2001
National Academy of Sciences of Armenia
1998-2001
Centre d’Investigació i Desenvolupament
1999
Memapsin 2 (β-secretase) is a membrane-associated aspartic protease involved in the production of β-amyloid peptide Alzheimer's disease and major target for drug design. We determined crystal structure domain human memapsin complexed to an eight-residue inhibitor at 1.9 angstrom resolution. The active site more open less hydrophobic than that other proteases. subsite locations from S 4 ′ are well defined. A kink chain P change direction 3 may be mimicked provide selectivity.
The endothelial cell protein C receptor (EPCR) shares ∼20% sequence identity with the major histocompatibility complex class 1/CD1 family of molecules, accelerates thrombin-thrombomodulin-dependent generation activated C, a natural anticoagulant, binds to neutrophils, and can undergo translocation from plasma membrane nucleus. Blocking C/activated binding inhibits not only activation but ability host respond appropriately bacterial challenge, exacerbating both coagulant inflammatory...
γ-Glutamyl transpeptidase 1 (GGT1) is a cell surface, N-terminal nucleophile hydrolase that cleaves glutathione and other γ-glutamyl compounds. GGT1 expression essential in cysteine homeostasis, its induction has been implicated the pathology of asthma, reperfusion injury, cancer. In this study, we report four new crystal structures human (hGGT1) show conformational changes within active site as enzyme progresses from free to inhibitor-bound tetrahedral transition states finally...
GTPase domain crystal structures of Rab5a wild type and five variants with mutations in the phosphate-binding loop are reported here at resolutions up to 1.5 Å. Of particular interest, A30P mutant was crystallized complexes GDP, GDP+AlF<sub>3</sub>, authentic GTP, respectively. The other variant crystals were obtained a non-hydrolyzable GTP analog, GppNHp. All solved same form, providing an unusual opportunity compare small GTPases different catalytic rates. exhibits dramatically reduced...
Abstract Bile‐salt activated lipase (BAL) is a páncreatic enzyme that digests variety of lipids in the small intestine. A distinct property BAL its dependency on bile salts hydrolyzing substrates long acyl chains or bulky alcoholic motifs. crystal structure catalytic domain human (residues 1‐538) with two surface mutations (N186D and A298D), which were introduced attempting to facilitate crystallization, has been determined at 2.3 Å resolution. The form belongs space group P2 1 2 one monomer...
The outer mitochondrial membrane isoform of mammalian cytochrome b5 (OM b5) is considerably more stable than its microsomal counterpart (Mc b5), whereas the corresponding apoproteins and Mc apo-b5) exhibit similar stability. OM apo-b5 are also in that their empty heme-binding pockets (core 1) highly disordered but remainder each apoprotein 2) displays substantial hololike structure. Core 1 residue 71 leucine all known b5's serine proteins. Replacing Leu-71 rat (rOM) with Ser has been shown...
GGT (γ-glutamyl transpeptidase) is an essential enzyme for maintaining cysteine homoeostasis, leukotriene synthesis, metabolism of glutathione conjugates and catabolism extracellular glutathione. Overexpression has been implicated in many pathologies, clinical inhibitors are under development use the treatment asthma, cancer other diseases. Inhibitors generally characterized using synthetic substrates. The present study uncompetitive GGT, revealed that potency with which compounds inhibit...
Two distinct forms of cytochrome b5 exist in the rat hepatocyte. One is associated with membrane endoplasmic reticulum (microsomal, or Mc, cyt b5) while other outer liver mitochondria (OM b5). Rat OM b5, only identified so far, has a significantly more negative reduction potential and substantially stable toward chemical thermal denaturation than Mc cytochromes b5. In addition, hemin kinetically trapped but not proteins. As result, no transfer from to apomyoglobin observed at pH values as...
The 2.6 Å (1 Å=0.1 nm) resolution structure has been determined for the glycosylated Fab (fragment antigen binding) of an IgM (Yvo) obtained from a subject with Waldenström's macroglobulinaemia. Dynamic light scattering was used to estimate gel point and monitor formation ordered hydroscopic Yvo upon cooling. If cryoglobulin forms gels in peripheral tissues organs, associated swelling damage microvasculature can result considerable morbidity mortality. three-dimensional branched N-linked...
The structure-based design, synthesis, and X-ray structure of protein–ligand complexes exceptionally potent selective β-secretase inhibitors are described. designed specifically to interact with S1′ active site residues provide selectivity over memapsin 1 cathepsin D. Inhibitor 5 has exhibited exceedingly inhibitory activity (Ki = 17 pM) high BACE 2 (>7000-fold) D (>250000-fold). A crystal revealed important molecular insight into these selectivities. These interactions may serve as an guide...
The X-ray structure of an immunoglobulin light-chain dimer isolated from the urine as a `Bence-Jones protein' patient with multiple myeloma and amyloidosis (Sea) was determined at 1.94 Å resolution refined to R Rfree factors 0.22 0.25, respectively. This `amyloidogenic' protein crystallized in orthorhombic P212121 space group unit-cell parameters = 48.28, b 83.32, c 112.59 100 K. In vital organs (heart kidneys), equivalent urinary produced fibrillar amyloid deposits which were fatal patient....
Circulating antiplasmin-cleaving enzyme (APCE), a prolyl-specific serine proteinase, is essentially identical to membrane-inserted fibroblast activation protein (FAP) that transiently expressed during epithelial-derived cancer growth. Human precursive alpha(2)-antiplasmin (Met-alpha(2)AP), the only known physiologic substrate for APCE, cleaved N-terminally Asn-alpha(2)AP rapidly cross-linked fibrin and protects it from digestion by plasmin. Identifying specific inhibitor of APCE/FAP...
Streptokinase (SK) is a thrombolytic agent widely used for the clinical treatment of clotting disorders such as heart attack. The based on ability SK to bind plasminogen (Pg) or plasmin (Pm), forming complexes that proteolytically activate other Pg molecules Pm, which carries out fibrinolysis. contains three major domains. N-terminal domain, SKα, provides complex with substrate recognition towards Pg. SKα unique mobile loop, residues 45–70, absent in corresponding domains bacterial...
Mammalian type B (mitochondrial) b5 cytochromes exhibit greater amino acid sequence diversity than their A (microsomal) counterparts, as exemplified by the proteins from human (hCYB5B) and rat (rCYB5B). The comparison of X-ray crystal structures hCYB5B rCYB5B reported herein reveals a striking difference in packing involving five-strand β-sheet, which can be attributed to fully buried residue 21 strand β4. bulk Leu21 that Thr21 results substantial displacement first two residues β5,...
Intense efforts are underway to identify inhibitors of the enzyme gamma-glutamyl transpeptidase 1 (GGT1) which cleaves extracellular compounds and contributes pathology asthma, reperfusion injury cancer. The glutamate analog, 6-diazo-5-oxo-norleucine (DON), inhibits GGT1. DON also many essential glutamine metabolizing enzymes rendering it too toxic for use in clinic as a GGT1 inhibitor. We investigated molecular mechanism human (hGGT1) inhibition by determine possible strategies increasing...
GGAs are a family of vesicle-coating regulatory proteins that function in intracellular protein transport. A GGA molecule contains four domains, each mediating interaction with other carrying out The GAT domain has been identified as the structural entity binds membrane-bound ARF, molecular switch regulating vesicle−coat assembly. It also directly interacts rabaptin5, an essential component endosome fusion. 2.8 Å resolution crystal structure human GGA1 is reported here. helices and elongated...