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The Structural Basis for Modular Nonribosomal Peptide Synthesis

模块化非核糖体肽合成的结构基础

基本信息

批准号：
9006608
负责人：
ANDREW M GULICK
金额：
$ 40.56万
依托单位：
HAUPTMAN-WOODWARD MEDICAL RESEARCH INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9006608
关键词：
Acids Active Sites Address Affect Amino Acids Antibiotic-Associated Colitis Antineoplastic Agents Architecture Bacteria Benzodiazepines Binding Biochemical Bleomycin Breathing Carrier Proteins Catalytic Domain Cells Chemicals Chemistry Cytotoxin Engineering Enzymatic Biochemistry Enzymes Equilibrium Family Gramicidin Human Individual Klebsiella oxytoca Length Ligands Molecular Molecular Conformation Monobactams Natural Products Nature Operon Pantetheine Pathogenesis Penicillins Peptide Antibiotics Peptide Synthesis Peptides Pharmacologic Substance Physical condensation Plants Play Production Protein Engineering Proteins Reaction Role Rotation Series Site Source Specificity Structural Biochemistry Structure Structure-Activity Relationship Substrate Specificity System Techniques Tertiary Protein Structure Testing Vancomycin Variant Virulence Factors Work adenylate base beta-Lactams cofactor commensal microbes enzyme activity fascinate fungus inhibitor/antagonist leinamycin nocardicin novel peptide synthase polypeptide public health relevance structural biology

项目摘要

DESCRIPTION (provided by applicant): Natural products are a rich source of pharmaceutically active compounds. One class of natural products are produced by the non-ribosomal peptide synthetases (NRPSs) through a fascinating modular, multidomain architecture. During synthesis, the peptide intermediates are bound to an integrated carrier protein that is delivered in a coordinated manner to neighboring catalytic domains. A complete understanding of the NRPS structural enzymology, including the active sites and the domain interfaces, would allow the identification of novel products both through analysis and prediction of uncharacterized biosynthetic clusters and the engineering of novel chemical moieties into previously identified NRPSs. To continue our structural interrogation of NRPSs, we will determine structures of NRPS multidomain enzymes, including full-length modules, with informative ligands. Our studies will address multiple NRPS systems that perform standard and unusual peptide syntheses. We will additionally examine the structural basis of a family of small auxiliary proteins that enhance NRPS adenylation domains. And finally, we will examine cytotoxin production from a novel NRPS system from a human commensal bacteria. These studies will use biochemical, biophysical, structural, and chemical techniques to continue our work to provide a complete structural description of the active sites and the domain choreography of the modular NRPS enzymes.