2VD4

Structure of small-molecule inhibitor of Glmu from Haemophilus influenzae reveals an allosteric binding site

2VD4 の概要

• エントリーDOI: 10.2210/pdb2vd4/pdb
• 関連するPDBエントリー: 2V0H 2V0I 2V0J 2V0K 2V0L
• 分子名称: BIFUNCTIONAL PROTEIN GLMU, 4-chloro-N-(3-methoxypropyl)-N-[(3S)-1-(2-phenylethyl)piperidin-3-yl]benzamide, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: glmu, inhibitor, magnesium, cell shape, peptidoglycan synthesis, allosteric, transferase, active site, metal-binding, cell wall biogenesis/degradation, multifunctional enzyme, nucleotidyltransferase, acyltransferase, uridyltransferase
• 由来する生物種: HAEMOPHILUS INFLUENZAE
• 細胞内の位置: Cytoplasm (By similarity): P43889
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 50924.64

構造登録者

Mochalkin, I.,Lightle, S.,McDowell, L. (登録日: 2007-09-28, 公開日: 2008-01-15, 最終更新日: 2023-12-13)

主引用文献

Mochalkin, I.,Lightle, S.,Narasimhan, L.,Bornemeier, D.,Melnick, M.,Vanderroest, S.,Mcdowell, L.
Structure of a Small-Molecule Inhibitor Complexed with Glmu from Haemophilus Influenzae Reveals an Allosteric Binding Site.
Protein Sci., 17:577-, 2008

PubMed Abstract: 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 A 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 (IC(50) approximately 18 microM 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.

PubMed: 18218712
DOI: 10.1110/PS.073271408

実験手法

X-RAY DIFFRACTION (1.9 Å)