Crystallographic Analysis of GHMP kinases

GHMP 激酶的晶体学分析

• 批准号: 6931004
• 负责人: HONG ZHANG
• 金额: $ 21.02万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-07 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931004
• 关键词: X ray crystallography; alcohol phosphotransferase; bacteria; bacterial proteins; biochemical evolution; computer simulation; conformation; crystallization; enzyme inhibitors; enzyme substrate analog; enzyme substrate complex; fungal proteins; intermolecular interaction; magnesium ion; model design /development; molecular cloning; molecular dynamics; molecular site; phosphorylation; physical model; protein folding; protein purification; protein structure function; proteomics; structural biology; yeasts

DESCRIPTION: (provided by applicant) The GHMP class of small metabolite kinases participates in several essential metabolic processes, such as glycolysis, amino acid biosynthesis, and sterol biosynthesis. Currently, the GHMP superfamily contains more than 170 proteins, representing about 12-13 different functions, including galactokinases, homoserine kinases, mevalonate kinases, phosphomevalonate kinases (hence GHMP), mevalonate diphosphate decarboxylase, isopentenyl monophosphate kinase, and archaeal shikimate kinase. Deficiencies in GHMP enzyme activities cause auxotrophic phenotypes in bacteria and hereditary metabolic diseases in humans. Structural characterization of GHMP enzymes and their complexes with substrates is crucial for understanding the active site, catalytic mechanism, inhibition and regulation of these enzymes. The first three dimensional structure of a GHMP protein, the homoserine kinase (HK), revealed a novel nucleotide-binding fold and a unique ATP binding mode. The crystals of the ternary complex between HK and its substrates were also obtained. Structural analysis of the HK-substrate complexes will reveal the key catalytic residues in the phosphoryl transfer reaction and the residues responsible for the substrate specificity. To learn how GHMP-fold accommodates substrates of very different structures, other members in the GHMP superfamily are selected for the structural studies in a systematic approach. Diffracting crystals of the archaeal shikimate kinase have been obtained. Comparative analysis of the enzyme-substrate complexes from different members of the GHMP superfamily will reveal the structural determinants of the substrate specificity in each family, provide a foundation for the structure-base drug design, and further our understanding of the structure-function evolution of this important class of enzymes.

描述：（由申请人提供）小型代谢物激酶的GHMP类 参加几个基本代谢过程，例如糖酵解， 氨基酸的生物合成和固醇生物合成。目前，GHMP 超家族含有170多种蛋白质，代表约12-13个蛋白质 功能，包括半乳痛动酶，同层激酶，甲戊酸激酶， 磷酸化酸酯激酶（因此GHMP），甲甲酸二磷酸二羧酸酯酶，二羧酸酯酶，二羧酸酯酶 异戊烯基单磷酸激酶和古细胞光泽激酶。缺陷 在GHMP酶活性中，在细菌和 人类的遗传代谢疾病。 GHMP的结构表征 酶及其与底物的复合物对于理解 活性位点，催化机制，这些酶的抑制和调节。 GHMP蛋白的前三维结构，同色激酶 （HK）揭示了一种新型的核苷酸结合折叠和独特的ATP结合模式。 香港与其底物之间的三元络合物的晶体也是 获得。 HK-Substrate复合物的结构分析将揭示关键 磷酸化转移反应中的催化残基和残基 负责底物特异性。了解GHMP折叠的容纳方式 GHMP超家族中的其他成员的底物非常不同 以系统的方法选择进行结构研究。衍射 已经获得了古细菌激酶的晶体。比较 分析GHMP不同成员的酶基底络合物 超家族将揭示基材的结构决定因素 每个家庭的特异性为结构基准药物提供基础 设计，进一步我们对结构功能演变的理解 这一重要类的酶。