PDBsum entry 4z0g

Oxidoreductase

PDB id: 4z0g

Contents

Protein chains

384 a.a.

Ligands

5GP ×4

GOL ×2

Metals

__K ×2

Waters ×645

PDB id:

4z0g

Name:

Oxidoreductase

Title:

Structure of the impdh from ashbya gossypii bound to gmp

Structure:

Inosine-5'-monophosphate dehydrogenase,inosine-5'- monophosphate dehydrogenase. Chain: a, b. Fragment: unp residues 1-119,unp residues 236-522. Synonym: impdh,impdh. Engineered: yes. Mutation: yes

Source:

Ashbya gossypii (strain atcc 10895 / cbs 109.51 / fgsc 9923 / nrrl y-1056). Organism_taxid: 284811. Gene: agos_aer117w. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

1.25Å R-factor: 0.125 R-free: 0.148

Authors:

R.M.Buey,J.M.De Pereda,J.L.Revuelta

Key ref:

R.M.Buey et al. (2015). Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases. Nat Commun, 6, 8923. PubMed id: 26558346 DOI: 10.1038/ncomms9923

Date:

26-Mar-15 Release date: 25-Nov-15

Protein chains

Q756Z6  (Q756Z6_ASHGO) -  Inosine-5'-monophosphate dehydrogenase from Eremothecium gossypii (strain ATCC 10895 / CBS 109.51 / FGSC 9923 / NRRL Y-1056)

Seq: 522 a.a.

Struc: 384 a.a.

Enzyme reactions

• Enzyme class: E.C.1.1.1.205 - Imp dehydrogenase.
• Pathway: AMP and GMP Biosynthesis
• Reaction: IMP + NAD⁺ + H2O = XMP + NADH + H⁺

IMP + NAD(+) (Bound ligand (Het Group name = 5GP) matches with 95.83% similarity) + H2O = XMP + NADH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/ncomms9923

Nat Commun 6:8923 (2015)

PubMed id: 26558346

Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases.

R.M.Buey, R.Ledesma-Amaro, A.Velázquez-Campoy, M.Balsera, M.Chagoyen, J.M.de Pereda, J.L.Revuelta.

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.