4z0g

From Proteopedia

Structure of the IMPDH from Ashbya gossypii bound to GMP

Structural highlights

4z0g is a 2 chain structure with sequence from Eremothecium gossypii ATCC 10895. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.25Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q756Z6_ASHGO Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth.[HAMAP-Rule:MF_03156]

Publication Abstract from PubMed

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.

Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases.,Buey RM, Ledesma-Amaro R, Velazquez-Campoy A, Balsera M, Chagoyen M, de Pereda JM, Revuelta JL Nat Commun. 2015 Nov 12;6:8923. doi: 10.1038/ncomms9923. PMID:26558346^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Buey RM, Ledesma-Amaro R, Velazquez-Campoy A, Balsera M, Chagoyen M, de Pereda JM, Revuelta JL. Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases. Nat Commun. 2015 Nov 12;6:8923. doi: 10.1038/ncomms9923. PMID:26558346 doi:http://dx.doi.org/10.1038/ncomms9923