1EEP

2.4 A RESOLUTION CRYSTAL STRUCTURE OF BORRELIA BURGDORFERI INOSINE 5'-MONPHOSPHATE DEHYDROGENASE IN COMPLEX WITH A SULFATE ION

Summary for 1EEP

• Entry DOI: 10.2210/pdb1eep/pdb
• Descriptor: INOSINE 5'-MONOPHOSPHATE DEHYDROGENASE, SULFATE ION (3 entities in total)
• Functional Keywords: alpha-beta barrel, tim barrel, impdh, imp dehydrogenase, loop-6, purine biosynthesis, oxidoreductase
• Biological source: Borrelia burgdorferi (Lyme disease spirochete)
• Total number of polymer chains: 2
• Total formula weight: 87847.17

Authors

McMillan, F.M.,Cahoon, M.,White, A.,Hedstrom, L.,Petsko, G.A.,Ringe, D. (deposition date: 2000-02-01, release date: 2000-03-29, Last modification date: 2024-02-07)

Primary citation

McMillan, F.M.,Cahoon, M.,White, A.,Hedstrom, L.,Petsko, G.A.,Ringe, D.
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.
Biochemistry, 39:4533-4542, 2000

PubMed 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.

PubMed: 10758003
DOI: 10.1021/bi992645l

Experimental method

X-RAY DIFFRACTION (2.4 Å)