5DL1

ClpP from Staphylococcus aureus in complex with AV145

5DL1 の概要

• エントリーDOI: 10.2210/pdb5dl1/pdb
• 関連するPDBエントリー: 3V5E
• 分子名称: ATP-dependent Clp protease proteolytic subunit, 1-(propan-2-yl)-N-{[2-(thiophen-2-yl)-1,3-oxazol-4-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (2 entities in total)
• 機能のキーワード: hydrolase-hydrolase inhibitor complex, caseinolytic protease, allosteric regulation, binding analysis, hydrolase
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 14
• 化学式量合計: 306655.38

構造登録者

Vielberg, M.-T.,Groll, M. (登録日: 2015-09-04, 公開日: 2015-11-25, 最終更新日: 2024-01-10)

主引用文献

Pahl, A.,Lakemeyer, M.,Vielberg, M.T.,Hackl, M.W.,Vomacka, J.,Korotkov, V.S.,Stein, M.L.,Fetzer, C.,Lorenz-Baath, K.,Richter, K.,Waldmann, H.,Groll, M.,Sieber, S.A.
Reversible Inhibitors Arrest ClpP in a Defined Conformational State that Can Be Revoked by ClpX Association.
Angew.Chem.Int.Ed.Engl., 54:15892-15896, 2015

PubMed Abstract: Caseinolytic protease P (ClpP) is an important regulator of Staphylococcus aureus pathogenesis. A high-throughput screening for inhibitors of ClpP peptidase activity led to the identification of the first non-covalent binder for this enzyme class. Co-crystallization of the small molecule with S. aureus ClpP revealed a novel binding mode: Because of the rotation of the conserved residue proline 125, ClpP is locked in a defined conformational state, which results in distortion of the catalytic triad and inhibition of the peptidase activity. Based on these structural insights, the molecule was optimized by rational design and virtual screening, resulting in derivatives exceeding the potency of previous ClpP inhibitors. Strikingly, the conformational lock is overturned by binding of ClpX, an associated chaperone that enables proteolysis by substrate unfolding in the ClpXP complex. Thus, regulation of inhibitor binding by associated chaperones is an unexpected mechanism important for ClpP drug development.

PubMed: 26566002
DOI: 10.1002/anie.201507266

実験手法

X-RAY DIFFRACTION (3 Å)