Počet záznamů: 1
Complex allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase by purine nucleotides
- 1.
SYSNO ASEP 0581637 Druh ASEP A - Abstrakt Zařazení RIV O - Ostatní Název Complex allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase by purine nucleotides Tvůrce(i) Bulvas, Ondřej (UOCHB-X) ORCID
Knejzlík, Zdeněk (UOCHB-X)
Kouba, Tomáš (UOCHB-X)
Pichová, Iva (UOCHB-X) RID, ORCIDAkce Discussions in Structural Molecular Biology /19./ and User Meeting of CIISB (Czech Infrastructure for Integrative Structural Biology) /6./ Datum konání 23.03.2023 - 25.03.2023 Místo konání Nové Hrady Země CZ - Česká republika Typ akce EUR Jazyk dok. eng - angličtina Klíč. slova allosteric regulation ; inosine-5′-monophosphate dehydrogenase (IMPDH) ; cryo-EM analysis Obor OECD Biochemistry and molecular biology CEP LX22NPO5103 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Výzkumná infrastruktura CIISB II - 90127 - Masarykova univerzita Institucionální podpora UOCHB-X - RVO:61388963 Anotace Inosine-5′-monophosphate dehydrogenase (IMPDH) is a crucial purine metabolism enzyme that is well established as a potential drug target against mycobacterial infections. However, most previous biochemical and structural studies were performed with IMPDH lacking its regulatory CBS domain, which binds allosteric regulators influencing the activity of IMPDH. This project aims to describe the allosteric regulation of full-length IMPDH and its underlying molecular mechanism. First, we isolated full-length and ΔCBS variants of IMPDH from Mycobacterium smegmatis and performed a detailed in vitro biochemical characterisation. Testing the impact of selected purine nucleotides on IMPDH activity indicated an unexpected regulatory effect of nucleotide ligands at biologically relevant concentrations. Next, to overcome problems with the X-ray crystallography approach, we utilised single particle cryo-EM analysis and, up to now, successfully obtained a series of datasets of IMPDH in complex with its allosteric regulators. Preliminary data suggest structural changes in the active/inhibited forms of IMPDH, which are triggered by the mode of binding of nucleotide ligands to the CBS domain. This might enable us to unravel the mechanism of interdomain crosstalk that leads to changes in the catalytic core of the enzyme. Such a mechanistic insight could contribute to the design of novel antimycobacterial IMPDH-targeting drugs. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2024 Elektronická adresa https://www.xray.cz/setkani/abst2023/630.htm
Počet záznamů: 1