Crystallographic Analysis of GHMP kinases

描述：(申请人提供)GHMP类小分子代谢物激酶 参与几个重要的代谢过程，如糖酵解， 氨基酸生物合成和甾醇生物合成。目前，温室气体排放计划 超家族包含170多种蛋白质，代表大约12-13种不同的 功能，包括半乳糖激酶酶、高丝氨酸激酶、甲氧丙酮酸激酶、 磷酸戊酸激酶(因此是GHMP)、甲氧戊酸二磷酸脱羧酶、 异戊烯基单磷酸激酶和古代莽草酸激酶。缺陷 在GHMP中，酶活性导致细菌和 人类的遗传性代谢性疾病。GHMP的结构表征 酶及其与底物的络合物对于理解 这些酶的活性部位、催化机制、抑制和调节。 GHMP蛋白的第一个三维结构--高丝氨酸激酶 (HK)，揭示了一个新的核苷酸结合折叠和独特的ATP结合模式。 HK与其底物的三元络合物的晶体也 获得。对香港底物络合物的结构分析将揭示关键 磷酰化转移反应中的催化残留物及其残留物 负责底物的专一性。要了解GHMP-Fold如何适应 具有非常不同结构的底物，GHMP超家族中的其他成员 被选中进行系统的结构研究。绕射 古菌莽草酸激酶的晶体已被获得。比较 GHMP不同成员的酶-底物复合体的分析 超家族将揭示底物的结构决定因素 在每个家族中具有特异性，为构型药物提供了基础 设计，并进一步理解结构-功能的演变 这类重要的酶。

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.