4DF6

Crystal Structure of the inhibitor NXL104 Covalent Adduct with TB B-lactamase

4DF6 の概要

• エントリーDOI: 10.2210/pdb4df6/pdb
• 関連するPDBエントリー: 3NY4
• 分子名称: Beta-lactamase, PHOSPHATE ION, (2S,5R)-1-formyl-5-[(sulfooxy)amino]piperidine-2-carboxamide, ... (4 entities in total)
• 機能のキーワード: penicillin binding protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28729.92

構造登録者

Hazra, S.,Blanchard, J. (登録日: 2012-01-23, 公開日: 2012-07-18, 最終更新日: 2024-10-09)

主引用文献

Xu, H.,Hazra, S.,Blanchard, J.S.
NXL104 irreversibly inhibits the {beta}-lactamase from Mycobacterium tuberculosis.
Biochemistry, 51:4551-4557, 2012

PubMed Abstract: NXL104 is a novel β-lactamase inhibitor with a non-lactam structural scaffold. Our kinetic and mass spectrometric analysis demonstrates that NXL104 quantitatively inhibits BlaC, the only chromosomally encoded β-lactamase from Mycobacterium tuberculosis, by forming a carbamyl adduct with the enzyme. The inhibition efficiency (k(2)/K) of NXL104 was shown to be more than 100-fold lower than that of clavulanate, a classical β-lactamase inhibitor, which is probably caused by the bulky rings of NXL104. However, the decarbamylation rate constant (k(3)) was determined to be close to zero. The BlaC-NXL104 adduct remained stable for at least 48 h, while the hydrolysis of the BlaC-clavulanate adduct was observed after 2 days. The three-dimensional crystal structure of the BlaC--NXL104 carbamyl adduct was determined at a resolution of 2.3 Å. Interestingly, the sulfate group of NXL104 occupies the position of a phosphate ion in the structure of the BlaC-clavulanate adduct and is hydrogen bonded to residues Ser128, Thr237, and Thr239. Favorable interactions are also seen in the electrostatic potential map. We propose that these additional interactions, as well as the intrinsic stability of the carbamyl linkage, contribute to the extraordinary stability of the BlaC-NXL104 adduct.

PubMed: 22587688
DOI: 10.1021/bi300508r

実験手法

X-RAY DIFFRACTION (2.29 Å)