Work

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

Year: 2025

Type: article

Abstract: Inosine-5′-monophosphate dehydrogenase (IMPDH), a key enzyme in bacterial purine metabolism, plays an essential role in the synthesis 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 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 MsmIMPDH, potentially informing the development of IMPDH-targeted drugs.

Source: Journal of Structural Biology

DOI: 10.1016/j.jsb.2025.108198

Authors: Ondřej Bulvas, Zdeněk Knejzlík, Anatolij Filimoněnko, Tomáš Kouba, Iva Pichová

Institution: Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry

Language: English

Topic: Biochemical and Molecular Research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: hybrid

Estimated APC paid: $4,350

Funders: Ministerstvo Školství, Mládeže a Tělovýchovy, Masarykova Univerzita