A5056993258- Protein Kinase Regulation and GTPase Signaling
- Enzyme Structure and Function
- Melanoma and MAPK Pathways
- Protein Structure and Dynamics
- Immune Cell Function and Interaction
- Ferroelectric and Piezoelectric Materials
- Herpesvirus Infections and Treatments
- Nuclear Physics and Applications
- Thermal and Kinetic Analysis
- Vector-borne infectious diseases
- Chemical and Physical Properties in Aqueous Solutions
- Metabolism, Diabetes, and Cancer
- Viral Infectious Diseases and Gene Expression in Insects
- Cardiac tumors and thrombi
- Neurofibromatosis and Schwannoma Cases
- Amino Acid Enzymes and Metabolism
- Acoustic Wave Resonator Technologies
- Cell death mechanisms and regulation
- Bartonella species infections research
- Immunodeficiency and Autoimmune Disorders
- Computational Drug Discovery Methods
- Optical and Acousto-Optic Technologies
- Magnetism in coordination complexes
- PI3K/AKT/mTOR signaling in cancer
- HIV Research and Treatment
GlaxoSmithKline (United States)
2024
North Carolina State University
2007-2021
National Institute of Allergy and Infectious Diseases
2014-2018
National Institutes of Health
2014-2018
Immungenetics (Germany)
2014
Brandeis University
2010
South Carolina State University
2007
Ras and its effector Raf are key mediators of the Ras/Raf/MEK/ERK signal transduction pathway. Mutants residue Q61 impair GTPase activity found prominently in human cancers. Yet mechanism through which contributes to catalysis has been elusive. It is thought position catalytic water molecule for nucleophilic attack on γ-phosphate GTP. However, we previously solved structure from crystals with symmetry space group R32 switch II disordered that present. Here present a wild-type calcium acetate...
Genetic defects in MOGS, the gene encoding mannosyl-oligosaccharide glucosidase (the first enzyme processing pathway of N-linked oligosaccharide), cause rare congenital disorder glycosylation type IIb (CDG-IIb), also known as MOGS-CDG. MOGS is expressed endoplasmic reticulum and involved trimming N-glycans. We evaluated two siblings with CDG-IIb who presented multiple neurologic complications a paradoxical immunologic phenotype characterized by severe hypogammaglobulinemia but limited...
RAS GTPase is a prototype for nucleotide-binding proteins that function by cycling between GTP and GDP, with hydrogen atoms playing an important role in the hydrolysis mechanism. It one of most well studied superfamily small GTPases, which has representatives wide range cellular functions. These share GTP-binding pocket highly conserved motifs promote to GDP. The neutron crystal structure presented here strongly supports protonated γ-phosphate at physiological pH. This counters notion...
Ras GTPase cycles between its active GTP-bound form promoted by GEFs and inactive GDP-bound GAPs to affect the control of various cellular functions. It is becoming increasingly apparent that subtle regulation state may occur through promotion substates mediated an allosteric switch mechanism induces a disorder order transition in II upon ligand binding at site. We show with high-resolution structures calcium acetate either dithioerythritol (DTE) or dithiothreitol (DTT) soaked into...
CD4 and chemokine receptors mediate HIV-1 attachment entry. They are, however, insufficient to explain the preferential viral infection of central memory T cells. Here, we identify L-selectin (CD62L) as a adhesion receptor on CD4+ The binding envelope glycans facilitates HIV entry infection, expression cells supports their by HIV. Upon virus downregulates through shedding, resulting in an apparent loss Infected effector cells, remain competent cytokine production. Surprisingly, inhibition...
Varicella zoster virus (VZV) is the causative agent for chickenpox and herpes (HZ, shingles). HZ a debilitating disease affecting elderly immunocompromised populations. Glycoprotein E (gE) indispensable viral replication cell-to-cell spread primary target anti-VZV antibodies. Importantly, gE sole antigen in Shingrix, highly efficacious, AS01
Ras cycles between an active GTP bound form and inactive GDP form. While hydrolysis of to is intrinsically slow, we have discovered a GAP‐independent allosteric switch mechanism that results in ordering II, placing the catalytic Q61 site. This expected enhance rate through where acts as general base, abstracting proton from nucleophilic water molecule, shuttling it bridging molecule donates H‐bonds Y32 I II. would promote partial positive charge on analogous arginine finger GAP. In order...
Ras GTPase is a prototype for nucleotide-binding proteins that function as molecular switches in variety of cellular functions. The switch modulated by cycling between the inactive GDP bound form and active GTP form, regulated opposing actions guanine nucleotide exchange factors activating proteins. Both intrinsic GAP catalyzed hydrolysis on have been studied assuming phosphate groups are fully deprotonated at physiological pH, they known to be solution. We present neutron crystal structure...
Ras is a monomeric GTPase which in its GTP‐bound form can bind various effectors signal transduction pathways. Through interaction with the effector Raf and associated Ras/Raf/MEK/ERK cascade it directly involved control of cell proliferation thus implicated many human cancers. Switch I switch II undergo conformational transition during hydrolysis contains active site residues binding sites. In Ras/Raf complex only interaction. We have crystal has conformation seen disordered free contacts....
The Ras GTPase and its effector Raf are key mediators of the Ras/Raf/MEK/Erk signal transduction pathway, which plays a central role in cell growth malignant transformation. Mutants residue Q61 impair activity found prominently cancers. Yet mechanism through contributes to catalysis has been elusive. We have that Ras‐GppNHp crystal binds calcium acetate from crystallization mother liquor at site remote active most likely near membrane, resulting shift helix 3/loop 7 network H‐bonding...
Multiple solvent crystal structures of chymotrypsin were used to map the binding surface enzyme. Crystals grown in aqueous mother liquor crosslinked with gluteraldehyde and transferred a variety organic solvents, whose molecules are representative functional groups that might appear larger ligand. Crystal solved 60% acetonitrile, 70% glycerol, 75% isopropanol, t-butanol, 50% DMSO, 50%DMF, 1,4-dioxane, n-hexane, 50%cyclopentanol, cyclopentanone, 40% cyclohexanol cyclohexanone. The solvents...
Rap1a is a small monomeric GTPase in the Ras family. It was originally thought to be antagonist, but evidence has accumulated support its direct role cell proliferation and differentiation, as well transcriptional regulation through interaction with B-Raf. GTPases act molecular switches, which cycle between an active GTP bound inactive GDP form. hydrolysis linked conformational changes primarily switch I II that modulate interactions downstream effector proteins. The structure of...
GTPases are hydrolytic proteins that convert GTP to GDP and serve as bivalent switches, where the GTP‐bound state is active, GDP‐bound inactive. Although Ras archetypal GTPase, Rap1A closely related with 50% sequence homology similar tertiary structure; a key difference occurs at position 61. In Q61 participates in hydrolysis mechanism mutation leads oncogenesis, while T61 not thought be involved catalysis. The goal of this project explore active site method intrinsic hydrolysis. Two crystal...
GTPases are hydrolytic proteins that convert GTP into GDP and serve as bivalent switches, where the GTP-bound state is active GDP-bound inactive. Rap1A a GTPase with 50% sequence homology similar tertiary structure to archetypal Ras, key difference occurring at position 61. In Ras Q61 participates in hydrolysis mechanism mutation leads oncogenesis, while role of T61 not clear. The goal this project explore site its intrinsic hydrolysis. Two crystal structures were obtained differing...