4Z87: Structure of the IMP dehydrogenase from Ashbya gossypii bound to GDP

Citation:
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.
PDB ID: 4Z87Download
MMDB ID: 134395
PDB Deposition Date: 2015/4/8
Updated in MMDB: 2015/11
Experimental Method:
x-ray diffraction
Resolution: 2.25  Å
Source Organism:
Similar Structures:
Biological Unit for 4Z87: octameric; determined by software (PISA)
Molecular Components in 4Z87
Label Count Molecule
Proteins (8 molecules)
8
Inosine-5'-monophosphate Dehydrogenase
Molecule annotation
Chemicals (52 molecules)
1
8
2
28
3
8
4
8
* Click molecule labels to explore molecular sequence information.

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