Get FREE U.S. Shipping on $75 Orders*

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.

1 Star2 Stars3 Stars4 Stars5 Stars (No Ratings Yet)
Loading...

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.

Biochemistry. 2000 Apr 18;39(15):4533-42. Research Support, Non-U.S. Gov’t; Research Support, U.S. Gov’t, P.H.S.

ProHealth CBD Store

 

1 Star2 Stars3 Stars4 Stars5 Stars (No Ratings Yet)
Loading...



Leave a Reply