Conformational landscape of the mycobacterial inosine 5′-monophosphate dehydrogenase octamerization interface

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00618752" target="_blank" >RIV/61388963:_____/25:00618752 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:90127/25:00143918

Výsledek na webu

<a href="https://doi.org/10.1016/j.jsb.2025.108198" target="_blank" >https://doi.org/10.1016/j.jsb.2025.108198</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jsb.2025.108198" target="_blank" >10.1016/j.jsb.2025.108198</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Conformational landscape of the mycobacterial inosine 5′-monophosphate dehydrogenase octamerization interface

Popis výsledku v původním jazyce

Inosine 5'-monophosphate dehydrogenase (IMPDH), a key enzyme in bacterial purine metabolism, plays an essential role in the biosynthesis of guanine nucleotides and shows promise as a target for antimicrobial drug development. Despite its significance, the conformational dynamics and substrate-induced structural changes in bacterial IMPDH remain poorly understood, particularly with respect to its octameric assembly. Using cryo-EM, we present full-length structures of IMPDH from Mycobacterium smegmatis (MsmIMPDH) captured in a reaction intermediate state, revealing conformational changes upon substrate binding. The structures feature resolved flexible loops that coordinate the binding of the substrate, the cofactor, and the K+ ion. Our structural analysis identifies a novel octamerization interface unique to MsmIMPDH. Additionally, a previously unobserved barrellike density suggests potential self-interactions within the C-terminal regions, hinting at a regulatory mechanism tied to assembly and function of the enzyme. These data provide insights into substrate-induced conformational dynamics and novel interaction interfaces in MsmIMPDH, potentially informing the development of IMPDHtargeted drugs.

Název v anglickém jazyce

Conformational landscape of the mycobacterial inosine 5′-monophosphate dehydrogenase octamerization interface

Popis výsledku anglicky

Inosine 5'-monophosphate dehydrogenase (IMPDH), a key enzyme in bacterial purine metabolism, plays an essential role in the biosynthesis of guanine nucleotides and shows promise as a target for antimicrobial drug development. Despite its significance, the conformational dynamics and substrate-induced structural changes in bacterial IMPDH remain poorly understood, particularly with respect to its octameric assembly. Using cryo-EM, we present full-length structures of IMPDH from Mycobacterium smegmatis (MsmIMPDH) captured in a reaction intermediate state, revealing conformational changes upon substrate binding. The structures feature resolved flexible loops that coordinate the binding of the substrate, the cofactor, and the K+ ion. Our structural analysis identifies a novel octamerization interface unique to MsmIMPDH. Additionally, a previously unobserved barrellike density suggests potential self-interactions within the C-terminal regions, hinting at a regulatory mechanism tied to assembly and function of the enzyme. These data provide insights into substrate-induced conformational dynamics and novel interaction interfaces in MsmIMPDH, potentially informing the development of IMPDHtargeted drugs.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LX22NPO5103" target="_blank" >LX22NPO5103: Národní institut virologie a bakteriologie</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Structural Biology

ISSN

1047-8477

e-ISSN

1095-8657

Svazek periodika

217

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

9

Strana od-do

108198

Kód UT WoS článku

001453365500001

EID výsledku v databázi Scopus

2-s2.0-105000557172