PDBsum entry 1eep

Oxidoreductase

PDB id: 1eep

Contents

Protein chains

314 a.a. *

Ligands

SO4 ×2

Waters ×107

* Residue conservation analysis

References listed in PDB file

Key reference

• Title: Crystal structure at 2.4 a resolution of borrelia burgdorferi inosine 5'-Monophosphate dehydrogenase: evidence of a substrate-Induced hinged-Lid motion by loop 6.
• Authors: F.M.Mcmillan, M.Cahoon, A.White, L.Hedstrom, G.A.Petsko, D.Ringe.
• Ref.: Biochemistry, 2000, 39, 4533-4542. [DOI no: 10.1021/bi992645l]
• PubMed id: 10758003

Abstract

The conversion of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP) is the committed and rate-limiting reaction in de novo guanine nucleotide biosynthesis. Inosine 5'- monophosphate dehydrogenase (IMPDH) is the enzyme that catalyzes the oxidation of IMP to XMP with the concomitant reduction of nicotinamide adenine dinucleotide (from NAD(+) to NADH). Because of its critical role in purine biosynthesis, IMPDH is a drug design target for anticancer, antiinfective, and immunosuppressive chemotherapy. We have determined the crystal structure of IMPDH from Borrelia burgdorferi, the bacterial spirochete that causes Lyme disease, with a sulfate ion bound in the IMP phosphate binding site. This is the first structure of IMPDH in the absence of substrate or cofactor where the active-site loop (loop 6), which contains the essential catalytic residue Cys 229, is clearly defined in the electron density. We report that a seven residue region of loop 6, including Cys229, is tilted more than 6 A away from its position in substrate- or substrate analogue-bound structures of IMPDH, suggestive of a conformational change. The location of this loop between beta6 and alpha6 links IMPDH to a family of beta/alpha barrel enzymes known to utilize this loop as a functional lid during catalysis. Least-squares minimization, root-mean-square deviation analysis, and inspection of the molecular surface of the loop 6 region in the substrate-free B. burgdorferi IMPDH and XMP-bound Chinese hamster IMPDH show that loop 6 follows a similar pattern of hinged rigid-body motion and indicates that IMPDH may be using loop 6 to bind and sequester substrate and to recruit an essential catalytic residue.