4DLJ

Human p38 MAP kinase in complex with RL163

4DLJ の概要

• エントリーDOI: 10.2210/pdb4dlj/pdb
• 関連するPDBエントリー: 4DLI
• 分子名称: Mitogen-activated protein kinase 14, 2-phenyl-N~4~-(2-phenylethyl)quinazoline-4,7-diamine (3 entities in total)
• 機能のキーワード: map kinase insert, transferase, lipid binding pocket, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q16539
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41949.90

構造登録者

Gruetter, C.,Termathe, M. (登録日: 2012-02-06, 公開日: 2013-01-23, 最終更新日: 2023-09-13)

主引用文献

Getlik, M.,Simard, J.R.,Termathe, M.,Grutter, C.,Rabiller, M.,van Otterlo, W.A.,Rauh, D.
Fluorophore labeled kinase detects ligands that bind within the MAPK insert of p38alpha kinase.
Plos One, 7:e39713-e39713, 2012

PubMed Abstract: The vast majority of small molecules known to modulate kinase activity, target the highly conserved ATP-pocket. Consequently, such ligands are often less specific and in case of inhibitors, this leads to the inhibition of multiple kinases. Thus, selective modulation of kinase function remains a major hurdle. One of the next great challenges in kinase research is the identification of ligands which bind to less conserved sites and target the non-catalytic functions of protein kinases. However, approaches that allow for the unambiguous identification of molecules that bind to these less conserved sites are few in number. We have previously reported the use of fluorescent labels in kinases (FLiK) to develop direct kinase binding assays that exclusively detect ligands which stabilize inactive (DFG-out) kinase conformations. Here, we present the successful application of the FLiK approach to develop a high-throughput binding assay capable of directly monitoring ligand binding to a remote site within the MAPK insert of p38α mitogen-activated protein kinase (MAPK). Guided by the crystal structure of an initially identified hit molecule in complex with p38α, we developed a tight binding ligand which may serve as an ideal starting point for further investigations of the biological function of the MAPK insert in regulating the p38α signaling pathway.

PubMed: 22768308
DOI: 10.1371/journal.pone.0039713

実験手法

X-RAY DIFFRACTION (2.6 Å)