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

Le résumé fourni par la source

• Cryo-EM reveals the E-XMP* reaction intermediate of full-length Msm IMPDH. • Binding of IMP alone induces K + binding site formation and C-terminal folding. • A novel octamerization interface is observed in the compressed Msm IMPDH structure. • C-terminal regions self-interact, forming a central barrel in the absence of IMP. 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 ( Msm IMPDH) 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 Msm IMPDH. Additionally, a previously unobserved barrel-like 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 Msm IMPDH, potentially informing the development of IMPDH-targeted drugs.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.