PDBsum entry 4z0g

Oxidoreductase

PDB id: 4z0g

Contents

Protein chains

384 a.a.

Ligands

5GP ×4

GOL ×2

Metals

__K ×2

Waters ×645

References listed in PDB file

Key reference

• Title: Guanine nucleotide binding to the bateman domain mediates the allosteric inhibition of eukaryotic imp dehydrogenases.
• Authors: R.M.Buey, R.Ledesma-Amaro, A.Velázquez-Campoy, M.Balsera, M.Chagoyen, J.M.De pereda, J.L.Revuelta.
• Ref.: Nat Commun, 2015, 6, 8923. [DOI no: 10.1038/ncomms9923]
• PubMed id: 26558346

Abstract

Inosine-5'-monophosphate dehydrogenase (IMPDH) plays key roles in purine nucleotide metabolism and cell proliferation. Although IMPDH is a widely studied therapeutic target, there is limited information about its physiological regulation. Using Ashbya gossypii as a model, we describe the molecular mechanism and the structural basis for the allosteric regulation of IMPDH by guanine nucleotides. We report that GTP and GDP bind to the regulatory Bateman domain, inducing octamers with compromised catalytic activity. Our data suggest that eukaryotic and prokaryotic IMPDHs might have developed different regulatory mechanisms, with GTP/GDP inhibiting only eukaryotic IMPDHs. Interestingly, mutations associated with human retinopathies map into the guanine nucleotide-binding sites including a previously undescribed non-canonical site and disrupt allosteric inhibition. Together, our results shed light on the mechanisms of the allosteric regulation of enzymes mediated by Bateman domains and provide a molecular basis for certain retinopathies, opening the door to new therapeutic approaches.