6D4K

Crystal structure of L,D-transpeptidase 3 from Mycobacterium tuberculosis at 1.32 A resolution

6D4K の概要

• エントリーDOI: 10.2210/pdb6d4k/pdb
• 分子名称: Probable L,D-transpeptidase 3, CALCIUM ION (3 entities in total)
• 機能のキーワード: apo-form, transferase
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28121.46

構造登録者

Libreros, G.A.,Dias, M.V.B. (登録日: 2018-04-18, 公開日: 2019-02-27, 最終更新日: 2023-10-04)

主引用文献

Libreros-Zuniga, G.A.,Dos Santos Silva, C.,Salgado Ferreira, R.,Dias, M.V.B.
Structural Basis for the Interaction and Processing of beta-Lactam Antibiotics by l,d-Transpeptidase 3 (LdtMt3) from Mycobacterium tuberculosis.
ACS Infect Dis, 5:260-271, 2019

PubMed Abstract: Targeting Mycobacterium tuberculosis peptidoglycans with β-lactam antibiotics represents a strategy to address increasing resistance to antitubercular drugs. β-Lactams inhibit peptidoglycan synthases such as l,d-transpeptidases, a group of carbapenem-sensitive enzymes that stabilize peptidoglycans through 3 → 3 cross-links. M. tuberculosis encodes five l,d-transpeptidases (Ldt), of which Ldt is one of the less understood. Herein, we structurally characterized the apo and faropenem-acylated forms of Ldt at 1.3 and 1.8 Å resolution, respectively. These structures revealed a fold and catalytic diad similar to those of other Ldts enzymes, supporting its involvement in transpeptidation reactions despite divergences in active site size and charges. The Ldt-faropenem structure indicated that faropenem is degraded after Cys-246 acylation, and possibly only a β-OH-butyrate or an acetyl group (CHO) covalently attached to the enzyme remains, an observation that strongly supports the notion that Ldt is inactivated by β-lactams. Docking simulations with intact β-lactams predicted key Ldt residues that interact with these antibiotics. We also characterized the heat of acylation involved in the binding and reaction of Ldt for ten β-lactams belonging to four different classes, and imipenem had the highest inactivation constant. This work provides key insights into the structure, binding mechanisms, and degradation of β-lactams by Ldt, which may be useful for the development of additional β-lactams with potential antitubercular activity.

PubMed: 30556998
DOI: 10.1021/acsinfecdis.8b00244

実験手法

X-RAY DIFFRACTION (1.32 Å)