PDBsum entry: 1lrt

Oxidoreductase

PDB id: 1lrt

Contents

Protein chains

338 a.a. *

Ligands

BOG ×2

IMP ×4

TAD ×4

TRS ×12

Metals

__K ×4

Waters ×543

* Residue conservation analysis

PDB id:

1lrt

Name:

Oxidoreductase

Title:

Crystal structure of ternary complex of tritrichomonas foetus inosine-5'-monophosphate dehydrogenase: structural characterization of NAD+ site in microbial enzyme

Structure:

Inosine-5'-monophosphate dehydrogenase. Chain: a, b, c, d. Synonym: inosine-5'-monophosphate dehydrogenase, imp dehydrogenase, impdh, impd. Engineered: yes

Source:

Tritrichomonas foetus. Organism_taxid: 5724. Gene: impdh. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.20Å R-factor: 0.212 R-free: 0.246

Authors:

L.Gan,G.A.Petsko,L.Hedstrom

Key ref:

L.Gan et al. (2002). Crystal structure of a ternary complex of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase: NAD+ orients the active site loop for catalysis. Biochemistry, 41, 13309-13317. PubMed id: 12403633 DOI: 10.1021/bi0203785

Date:

15-May-02 Release date: 07-Jul-03

Protein chains

P50097  (IMDH_TRIFO) -  Inosine-5'-monophosphate dehydrogenase

Seq: 503 a.a.

Struc: 338 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.1.1.1.205 - Imp dehydrogenase.
• Pathway: AMP and GMP Biosynthesis
• Reaction: Inosine 5'-phosphate + NAD⁺ + H₂O = xanthosine 5'-phosphate + NADH

Inosine 5'-phosphate (Bound ligand (Het Group name = IMP) corresponds exactly) + NAD(+) + H(2)O = xanthosine 5'-phosphate + NADH

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

 Gene Ontology (GO) functional annotation 

• Biological process: metabolic process (2 terms)
• Biochemical function: catalytic activity (2 terms)

reference

DOI no: 10.1021/bi0203785

Biochemistry 41:13309-13317 (2002)

PubMed id: 12403633

Crystal structure of a ternary complex of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase: NAD+ orients the active site loop for catalysis.

L.Gan, G.A.Petsko, L.Hedstrom.

ABSTRACT

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the conversion of IMP to XMP with the reduction of NAD(+), which is the rate-limiting step in the biosynthesis of guanine nucleotides. IMPDH is a promising target for chemotherapy. Microbial IMPDHs differ from mammalian enzymes in their lower affinity for inhibitors such as mycophenolic acid (MPA) and thiazole-4-carboxamide adenine dinucleotide (TAD). Part of this resistance is determined by the coupling between nicotinamide and adenosine subsites in the NAD(+) binding site that is postulated to involve an active site flap. To understand the structural basis of the drug selectivity, we solved the X-ray crystal structure of the catalytic core domain of Tritrichomonas foetus IMPDH in complex with IMP and beta-methylene-TAD at 2.2 A resolution. Unlike previous structures of this enzyme, the active site loop is ordered in this complex, and the catalytic Cys319 is 3.6 A from IMP, in the same plane as the hypoxanthine ring. The active site loop forms hydrogen bonds to the carboxamide of beta-Me-TAD which suggests that NAD(+) promotes the nucleophillic attack of Cys319 on IMP. The interactions of the adenosine end of TAD are very different from those in the human enzyme, suggesting the NAD(+) site may be an exploitable target for the design of antimicrobial drugs. In addition, a new K(+) site is observed at the subunit interface. This site is adjacent to beta-Me-TAD, consistent with the link between the K(+) activation and NAD(+). However, contrary to the coupling model, the flap does not cover the adenosine subsite and remains largely disordered.