LAYING THE FOUNDATIONS FOR GENOMIC ENZYMOLOGY

为基因组酶学奠定基础

• 批准号: 8363593
• 负责人: PATRICIA CLEMENT BABBITT
• 金额: $ 1.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363593
• 关键词: Binding; Catalysis; Chemicals; Chemistry; Communities; Complex; Databases; Docking; Drug Design; Engineering; Enzymatic Biochemistry; Enzymes; Evolution; Family; Foundations; Funding; Genomics; Grant; Health; Human; Imagery; Informatics; Learning; Methodology; National Center for Research Resources; Nature; Principal Investigator; Protein Engineering; Proteins; Reaction; Research; Research Infrastructure; Resources; Source; Structure; Subgroup; United States National Institutes of Health; Variant; biocomputing; catalyst; chemical reaction; cofactor; cost; design; engineering design; enzyme model; inhibitor/antagonist; member; scaffold; small molecule

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Mechanistically diverse enzyme superfamilies represent sets of divergent proteins whose substrates, products and even overall functions can be substantially different. Divergent evolution of such broadly varied chemical reactions can be described by the chemistry-constrained model of enzyme evolution, in which nature re-engineers the ancestral scaffold for a variety of functions by conserving a fundamental chemical capability such as a partial reaction, while evolving variations in substrate binding, and therefore overall chemistry. This renewal proposal has four aims, which extend the progress achieved in the previous grant: 1) Investigate additional mechanistically diverse enzyme superfamilies to determine how the delivery of catalysis is constrained by the common catalytic module in each. We will also detail for each how new catalysts have arisen to perform a variety of functions. We expect the results to reveal general principles of enzyme design utilized in nature and identify specific rules applicable for functional inference and mechanistic understanding for each of the superfamilies investigated. This information will be made available to the scientific community via our ?Structure-Function Linkage Database (SFLD)?. 2) Identify sequence/structural differences that discriminate subgroups/families in characterized superfamilies to achieve more precision in functional inference than can be obtained by prediction of the superfamily-common functions alone. 3) Investigate superfamilies that utilize complex co-factors to learn how such superfamilies differ from the relatively more ?simple? types of superfamilies we have previously studied. These studies will focus first on superfamilies that use FAD cofactors. 4) Lay the groundwork for predicting promiscuity and new chemical reactions that could be supported by the catalytic modules studied in this proposal. Docking methodologies will be used to identify small molecules likely to bind or that could be turned over by superfamily members. The results will be added to the SFLD to aid others in inference of function, identification of inhibitors useful in structural characterization or drug design, and to guide protein engineering/design for applications to human health.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 机械上不同的酶超家族代表了一组不同的蛋白质，其底物，产物甚至整体功能可能会大不相同。这种广泛多样化的化学反应的发散演化可以通过化学受限的酶演化模型来描述，在这种模型中，自然界通过维护基本化学能力（例如部分反应），在底物结合中演变出来的变化，从而使各种功能重新设计了各种功能的祖先支架。该续签提案有四个目标，可以扩大上一笔赠款中取得的进展： 1）研究其他机械上不同的酶超家族，以确定催化的递送如何受到每个催化模块的约束。我们还将详细介绍每种新催化剂如何执行各种功能。我们预计结果将揭示自然界中使用的酶设计的一般原则，并确定适用于所研究的每个超家族的功能推断和机械理解的特定规则。该信息将通过我们的“结构 - 函数链接数据库（SFLD）”提供给科学界？ 2）确定序列/结构差异，这些序列/结构差异以特征性超家族区分亚组/家族，以实现功能推断的精度，而不是通过仅预测单独的超家族官方函数来获得。 3）调查使用复杂的副因素来了解这种超家族与相对更简单的超级家庭有何不同？我们以前研究过的超家族类型。这些研究将首先关注使用FAD辅助因子的超家族。 4）为预测该提案中研究的催化模块所支持的滥交和新的化学反应的基础。对接方法将用于识别可能结合的小分子，或者可能被超家族成员转换。结果将添加到SFLD中，以帮助他人推理功能，鉴定在结构表征或药物设计中有用的抑制剂，以及指导蛋白质工程/设计用于人类健康的蛋白质工程/设计。