2025/03/17 by Ondřej Bulvas, Zdeněk Knejzlı́k, Anatolij Filimoněnko +2 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Medicine · #Adenosine and Purinergic Signaling #Biochemical and Molecular Research #Cytomegalovirus and herpesvirus research
paper · doi:10.1016/j.jsb.2025.108198
openalex publication_date 2025/03/17 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/23
• 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.