5G15

Structure Aurora A (122-403) bound to activating monobody Mb1 and AMPPCP

5G15 の概要

• エントリーDOI: 10.2210/pdb5g15/pdb
• 関連するPDBエントリー: 5G16
• 分子名称: AURORA A KINASE, MB1 MONOBODY, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (6 entities in total)
• 機能のキーワード: transferase, aurora a, monobody, amppcp, kinase, activation, allostery, cell cycle, cancer
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 44180.82

構造登録者

Zorba, A.,Kutter, S.,Kern, D.,Koide, S.,Koide, A. (登録日: 2016-03-23, 公開日: 2018-03-14, 最終更新日: 2024-01-10)

主引用文献

Zorba, A.,Nguyen, V.,Koide, A.,Hoemberger, M.,Zheng, Y.,Kutter, S.,Kim, C.,Koide, S.,Kern, D.
Allosteric modulation of a human protein kinase with monobodies.
Proc.Natl.Acad.Sci.USA, 116:13937-13942, 2019

PubMed Abstract: Despite being the subject of intense effort and scrutiny, kinases have proven to be consistently challenging targets in inhibitor drug design. A key obstacle has been promiscuity and consequent adverse effects of drugs targeting the ATP binding site. Here we introduce an approach to controlling kinase activity by using monobodies that bind to the highly specific regulatory allosteric pocket of the oncoprotein Aurora A (AurA) kinase, thereby offering the potential for more specific kinase modulators. Strikingly, we identify a series of highly specific monobodies acting either as strong kinase inhibitors or activators via differential recognition of structural motifs in the allosteric pocket. X-ray crystal structures comparing AurA bound to activating vs inhibiting monobodies reveal the atomistic mechanism underlying allosteric modulation. The results reveal 3 major advantages of targeting allosteric vs orthosteric sites: extreme selectivity, ability to inhibit as well as activate, and avoidance of competing with ATP that is present at high concentrations in the cells. We envision that exploiting allosteric networks for inhibition or activation will provide a general, powerful pathway toward rational drug design.

PubMed: 31239342
DOI: 10.1073/pnas.1906024116

実験手法

X-RAY DIFFRACTION (2.06 Å)