4MXZ

Src M314L T338M double mutant bound to kinase inhibitor bosutinib

4MXZ の概要

• エントリーDOI: 10.2210/pdb4mxz/pdb
• 関連するPDBエントリー: 4MXO 4MXX 4MXY
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile (3 entities in total)
• 機能のキーワード: kinase, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane: P12931
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66506.17

構造登録者

Levinson, N.M.,Boxer, S.G. (登録日: 2013-09-26, 公開日: 2013-12-04, 最終更新日: 2024-02-28)

主引用文献

Levinson, N.M.,Boxer, S.G.
A conserved water-mediated hydrogen bond network defines bosutinib's kinase selectivity.
Nat.Chem.Biol., 10:127-132, 2014

PubMed Abstract: Kinase inhibitors are important cancer drugs, but they tend to display limited target specificity, and their target profiles are often challenging to rationalize in terms of molecular mechanism. Here we report that the clinical kinase inhibitor bosutinib recognizes its kinase targets by engaging a pair of conserved structured water molecules in the active site and that many other kinase inhibitors share a similar recognition mechanism. Using the nitrile group of bosutinib as an infrared probe, we show that the gatekeeper residue and one other position in the ATP-binding site control access of the drug to the structured water molecules and that the amino acids found at these positions account for the kinome-wide target spectrum of the drug. Our work highlights the importance of structured water molecules for inhibitor recognition, reveals a new role for the kinase gatekeeper and showcases an effective approach for elucidating the molecular origins of selectivity patterns.

PubMed: 24292070
DOI: 10.1038/nchembio.1404

実験手法

X-RAY DIFFRACTION (2.582 Å)