A5072187299- Enzyme Structure and Function
- Bacterial Genetics and Biotechnology
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- HIV Research and Treatment
- Biochemical and Molecular Research
- Protein Kinase Regulation and GTPase Signaling
- Enzyme-mediated dye degradation
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Microbial Natural Products and Biosynthesis
- Amino Acid Enzymes and Metabolism
- Genomics and Phylogenetic Studies
- Enzyme Production and Characterization
- Peptidase Inhibition and Analysis
- ATP Synthase and ATPases Research
- Cancer, Hypoxia, and Metabolism
- Plant Pathogenic Bacteria Studies
- Protein purification and stability
- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Pleural and Pulmonary Diseases
- Porphyrin Metabolism and Disorders
- Infectious Diseases and Tuberculosis
Incyte (United States)
2022-2025
Stanford University
2009-2018
SLAC National Accelerator Laboratory
2009-2018
Stanford Synchrotron Radiation Lightsource
2018
Scripps Research Institute
2008-2017
Joint Center for Structural Genomics
2008-2017
Franciscan University of Steubenville
2016-2017
International AIDS Vaccine Initiative
2015
Justus-Liebig-Universität Gießen
2014
Wilfrid Laurier University
2005
HIV-1 entry into CD4(+) target cells is mediated by cleaved envelope glycoprotein (Env) trimers that have been challenging to characterize structurally. Here, we describe the crystal structure at 4.7 angstroms of a soluble, Env trimer stabilized and antigenically near-native (termed BG505 SOSIP.664 gp140 trimer) in complex with potent broadly neutralizing antibody, PGT122. The shows prefusion state gp41, interaction between component gp120 gp41 subunits, how close association V1/V2/V3 loops...
Polysaccharide monooxygenases (PMOs) are secreted metalloenzymes that catalyze the oxidative degradation of polysaccharides in a copper-, oxygen-, and reductant-dependent manner. Cellulose-active fungal PMOs degrade cellulosic substrates to be utilized as carbon source for growth. To gain insight into PMO mechanism, role conserved residues copper coordination sphere was investigated. Here, we report active-site hydrogen-bonding motifs secondary MtPMO3*, C1-oxidizing from ascomycete fungus...
ABSTRACT We have determined the crystal structure of broadly neutralizing antibody (bnAb) AP33, bound to a peptide corresponding hepatitis C virus (HCV) E2 envelope glycoprotein antigenic site 412 423. Comparison with bnAb HCV1 same epitope reveals different angle approach antigen by AP33 and slight variation in its β-hairpin conformation epitope. These structures establish two modes binding that antibodies adopt neutralize diverse HCV.
The HIV-1 envelope gp160 glycoprotein (Env) is a trimer of gp120 and gp41 heterodimers that mediates cell entry the primary target humoral immune response. Broadly neutralizing antibodies (bNAbs) to have revealed multiple epitopes or sites vulnerability, but mapping most these incomplete owing paucity structural information on full epitope in context Env trimer. Here, crystal structure soluble BG505 SOSIP gp140 at 4.6 Å resolution with bNAbs 8ANC195 PGT128 reveals additional interactions...
Among broadly neutralizing antibodies to HIV, 10E8 exhibits greater breadth than most. Consequently, this antibody is the focus of prophylactic/therapeutic development. The epitope has been identified as conserved membrane proximal external region (MPER) gp41 subunit envelope (Env) viral glycoprotein and a major vaccine target. However, MPER may be laterally inserted into in Env prefusion form. Nevertheless, not reported have significant lipid-binding reactivity. Here we report x-ray...
CDK2 is a critical regulator of the cell cycle. For variety human cancers, dysregulation CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts develop inhibitors with clinical applications proved unsuccessful due challenges in achieving selectivity over off-target CDK isoforms associated toxicity. In this report, we describe discovery (4-pyrazolyl)-2-aminopyrimidines as potent class that display CDKs 1, 4, 6, 7, 9. SAR studies led identification compound 17,...
Abstract Bt DyP from Bacteroides thetaiotaomicron (strain VPI‐5482) and TyrA Shewanella oneidensis are dye‐decolorizing peroxidases (DyPs), members of a new family heme‐dependent recently identified in fungi bacteria. Here, we report the crystal structures BtDyP at 1.6 2.7 Å, respectively. assembles into hexamer, while dimer; dimerization interface is conserved between two proteins. Each monomer exhibits two‐domain, α+β ferredoxin‐like fold. A site for heme binding was computationally,...
Significance Maintenance and reprogramming of pluripotency are among the most important issues in stem cell biology regenerative medicine. Pluripotency is governed by several key transcription factors regulating other factors. Among these, regulation OCT4 NANOG (from Irish myth-ology Tír na nÓg) a critical interaction. We present here crystal structure human homeodomain complex with promoter DNA and, through series ration-ally designed mutations, we identify functional residues protein–DNA...
TyrA is a member of the dye-decolorizing peroxidase (DyP) family, new family heme-dependent recently identified in fungi and bacteria. Here, we report crystal structure complex with iron protoporphyrin (IX) at 2.3 A. dimer, each monomer exhibiting two-domain, alpha/beta ferredoxin-like fold. Both domains contribute to heme-binding site. Co-crystallization presence an excess chloride allowed for unambiguous location active site specific residues involved heme binding. The reveals Fe-His-Asp...
Dipeptidyl-peptidase VI from Bacillus sphaericus and YkfC subtilis have both previously been characterized as highly specific γ-d-glutamyl-l-diamino acid endopeptidases. The crystal structure of a ortholog cereus (BcYkfC) at 1.8 Å resolution revealed that it contains two N-terminal bacterial SH3 (SH3b) domains in addition to the C-terminal catalytic NlpC/P60 domain is ubiquitous very large family cell-wall-related cysteine peptidases. A bound reaction product (l-Ala-γ-d-Glu) enabled...
Abstract TM0077 from Thermotoga maritima is a member of the carbohydrate esterase family 7 and active on variety acetylated compounds, including cephalosporin C. activity confined to short‐chain acyl esters (C2–C3), optimal around 100°C pH 7.5. The positional specificity was investigated using 4‐nitrophenyl‐β‐ D ‐xylopyranoside monoacetates as substrates in β‐xylosidase‐coupled assay. hydrolyzes acetate at positions 2, 3, 4 with equal efficiency. No detected xylan or xylan, which implies...
The harvesting of protein crystals is almost always a necessary step in the determination structure using X-ray crystallographic techniques. However, are usually fragile and susceptible to damage during process. For this reason, crystal single that remains entirely dependent on skilled human intervention. Automation has been implemented majority other stages structure-determination pipeline, including cloning, expression, purification, crystallization data collection. gap automation between...
Catalytic modules of assembly-line polyketide synthases (PKSs) have previously been observed in two very different conformations—an "extended" architecture and an "arch-shaped" architecture—although the catalytic relevance neither has directly established. By use a fully human naïve antigen-binding fragment (Fab) library, high-affinity antibody was identified that bound to extended conformation PKS module, as verified by X-ray crystallography tandem size-exclusion chromatography–small-angle...
The inhibition of mutant KRAS proteins has emerged as a promising approach for treating KRAS-driven cancers, evidenced by the clinical success G12C inhibitors. G12D, most common mutant, promises significant expansion addressable patient population; however, reduced nucleophilicity aspartate compared to cysteine poses challenges in balancing sufficient potency with ADME properties support oral exposure. Herein, we describe discovery G12D inhibitor 23 (INCB159020), which achieves exposure...
Abstract Aim: This study examined the effect of oestrogen supplementation in rats on myogenic satellite cell quantities type I and II muscles following eccentric exercise. Methods: Gonad intact adult male divided into four groups, supplemented (25 mg pellet) control (EC), supplemented, exercised (EE), sham (no oestrogen) (SC) sham, (SE). After 1 week exposure EE SE animals performed 90 min intermittent downhill running (5 running/2 rest @−13.5° incline 17 m −1 speed). Seventy‐two hours later...
Pleckstrin homology (PH) domains have been identified only in eukaryotic proteins to date. We determined crystal structures for three members of an uncharacterized protein family (Pfam PF08000), which provide compelling evidence the existence PH-like bacteria (PHb). The first two contain a single PHb domain that forms dome-shaped, oligomeric ring with C(5) symmetry. third structure has additional helical hairpin attached at C-terminus and similar but much larger C(12) Thus, both molecular...
Membrane-attack complex/perforin (MACPF) proteins are transmembrane pore-forming that important in both human immunity and the virulence of pathogens. Bacterial MACPFs found diverse bacterial species, including most gut-associated Bacteroides species. The crystal structure a MACPF-domain-containing protein BT_3439 (Bth-MACPF) from B. thetaiotaomicron, predominant member mammalian intestinal microbiota, has been determined. Bth-MACPF contains membrane-attack domain two novel C-terminal...