6P1Y

Crystal structure of Mtb aspartate decarboxylase mutant M117I

6P1Y の概要

• エントリーDOI: 10.2210/pdb6p1y/pdb
• 分子名称: Aspartate 1-decarboxylase beta chain, Aspartate 1-decarboxylase alpha chain, AMMONIUM ION, ... (5 entities in total)
• 機能のキーワード: structural genomics, tb structural genomics consortium, tbsgc, lyase, poa, drug-resistance, mutant
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 16123.20

構造登録者

Sun, Q.,Li, X.,Sacchettini, J.C.,TB Structural Genomics Consortium (TBSGC) (登録日: 2019-05-20, 公開日: 2020-02-05, 最終更新日: 2024-10-23)

主引用文献

Sun, Q.,Li, X.,Perez, L.M.,Shi, W.,Zhang, Y.,Sacchettini, J.C.
The molecular basis of pyrazinamide activity on Mycobacterium tuberculosis PanD.
Nat Commun, 11:339-339, 2020

PubMed Abstract: Pyrazinamide has been a mainstay in the multidrug regimens used to treat tuberculosis. It is active against the persistent, non-replicating mycobacteria responsible for the protracted therapy required to cure tuberculosis. Pyrazinamide is a pro-drug that is converted into pyrazinoic acid (POA) by pyrazinamidase, however, the exact target of the drug has been difficult to determine. Here we show the enzyme PanD binds POA in its active site in a manner consistent with competitive inhibition. The active site is not directly accessible to the inhibitor, suggesting the protein must undergo a conformational change to bind the inhibitor. This is consistent with the slow binding kinetics we determined for POA. Drug-resistant mutations cluster near loops that lay on top of the active site. These resistant mutants show reduced affinity and residence time of POA consistent with a model where resistance occurs by destabilizing the closed conformation of the active site.

PubMed: 31953389
DOI: 10.1038/s41467-019-14238-3

実験手法

X-RAY DIFFRACTION (2.33 Å)