6VGQ

ClpP1P2 complex from M. tuberculosis with GLF-CMK bound to ClpP1

6VGQ の概要

• エントリーDOI: 10.2210/pdb6vgq/pdb
• 関連するPDBエントリー: 6VGK
• EMDBエントリー: 21197 21199
• 分子名称: ATP-dependent Clp protease proteolytic subunit 1, ATP-dependent Clp protease proteolytic subunit, Z-Gly-leu-phe-CH2Cl (3 entities in total)
• 機能のキーワード: complex, protease, clpp, tuberculosis, hydrolase
• 由来する生物種: Mycobacterium tuberculosis; 詳細
• タンパク質・核酸の鎖数: 21
• 化学式量合計: 304509.38

構造登録者

Ripstein, Z.A.,Vahidi, S.,Rubinstein, J.L.,Kay, L.E. (登録日: 2020-01-08, 公開日: 2020-03-18, 最終更新日: 2024-10-09)

主引用文献

Vahidi, S.,Ripstein, Z.A.,Juravsky, J.B.,Rennella, E.,Goldberg, A.L.,Mittermaier, A.K.,Rubinstein, J.L.,Kay, L.E.
An allosteric switch regulatesMycobacterium tuberculosisClpP1P2 protease function as established by cryo-EM and methyl-TROSY NMR.
Proc.Natl.Acad.Sci.USA, 117:5895-5906, 2020

PubMed Abstract: The 300-kDa ClpP1P2 protease from collaborates with the AAA+ (ATPases associated with a variety of cellular activities) unfoldases, ClpC1 and ClpX, to degrade substrate proteins. Unlike in other bacteria, all of the components of the Clp system are essential for growth and virulence of mycobacteria, and their inhibitors show promise as antibiotics. MtClpP1P2 is unique in that it contains a pair of distinct ClpP1 and ClpP2 rings and also requires the presence of activator peptides, such as benzoyl-leucyl-leucine (Bz-LL), for function. Understanding the structural basis for this requirement has been elusive but is critical for the rational design and improvement of antituberculosis (anti-TB) therapeutics that target the Clp system. Here, we present a combined biophysical and biochemical study to explore the structure-dynamics-function relationship in MtClpP1P2. Electron cryomicroscopy (cryo-EM) structures of apo and acyldepsipeptide-bound MtClpP1P2 explain their lack of activity by showing loss of a key β-sheet in a sequence known as the handle region that is critical for the proper formation of the catalytic triad. Methyl transverse relaxation-optimized spectroscopy (TROSY)-based NMR, cryo-EM, and biochemical assays show that, on binding Bz-LL or covalent inhibitors, MtClpP1P2 undergoes a conformational change from an inactive compact state to an active extended structure that can be explained by a modified Monod-Wyman-Changeux model. Our study establishes a critical role for the handle region as an on/off switch for function and shows extensive allosteric interactions involving both intra- and interring communication that regulate MtClpP1P2 activity and that can potentially be exploited by small molecules to target .

PubMed: 32123115
DOI: 10.1073/pnas.1921630117

実験手法

ELECTRON MICROSCOPY (3.5 Å)