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Published online before print January 24, 2008, 10.1110/ps.073271408
Protein Science (2008), 17:577-582. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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PROTEIN STRUCTURE REPORT

Structure of a small-molecule inhibitor complexed with GlmU from Haemophilus influenzae reveals an allosteric binding site

Igor Mochalkin1,2, Sandra Lightle1,3, Lakshmi Narasimhan1,4, Dirk Bornemeier1, Michael Melnick1, Steven VanderRoest1, and Laura McDowell1,2

1 Pfizer Inc., Michigan Laboratories, Ann Arbor, Michigan 48105, USA
2 Pfizer Inc., Groton, Connecticut 06340, USA
3 Pfizer, Inc., Chesterfield, Missouri 63017, USA
4 Pfizer Inc., San Diego, California 92121, USA

(RECEIVED September 30, 2007; FINAL REVISION November 26, 2007; ACCEPTED November 26, 2007)

N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU) is an essential enzyme in aminosugars metabolism and an attractive target for antibiotic drug discovery. GlmU catalyzes the formation of uridine-diphospho-N-acetylglucosamine (UDP-GlcNAc), an important precursor in the peptidoglycan and lipopolisaccharide biosynthesis in both Gram-negative and Gram-positive bacteria. Here we disclose a 1.9 Å resolution crystal structure of a synthetic small-molecule inhibitor of GlmU from Haemophilus influenzae (hiGlmU). The compound was identified through a high-throughput screening (HTS) configured to detect inhibitors that target the uridyltransferase active site of hiGlmU. The original HTS hit exhibited a modest micromolar potency (IC50 ~ 18 µM in a racemic mixture) against hiGlmU and no activity against Staphylococcus aureus GlmU (saGlmU). The determined crystal structure indicated that the inhibitor occupies an allosteric site adjacent to the GlcNAc-1-P substrate-binding region. Analysis of the mechanistic model of the uridyltransferase reaction suggests that the binding of this allosteric inhibitor prevents structural rearrangements that are required for the enzymatic reaction, thus providing a basis for structure-guided design of a new class of mechanism-based inhibitors of GlmU.

Keywords: uridyltransferase; allosteric inhibitors; mechanism; UDP-N-acetylglucosamine


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