1OUK

The structure of p38 alpha in complex with a pyridinylimidazole inhibitor

1OUK の概要

• エントリーDOI: 10.2210/pdb1ouk/pdb
• 関連するPDBエントリー: 1M7Q
• 分子名称: Mitogen-activated protein kinase 14, SULFATE ION, 4-[5-[2-(1-PHENYL-ETHYLAMINO)-PYRIMIDIN-4-YL]-1-METHYL-4-(3-TRIFLUOROMETHYLPHENYL)-1H-IMIDAZOL-2-YL]-PIPERIDINE, ... (4 entities in total)
• 機能のキーワード: map kinase, hydrophobic pocket, kinase domain, atp binding domain, transferase
• 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: 42601.57

構造登録者

Fitzgerald, C.E.,Patel, S.B.,Becker, J.W.,Cameron, P.M.,Zaller, D.,Pikounis, V.B.,O'Keefe, S.J.,Scapin, G. (登録日: 2003-03-24, 公開日: 2003-09-02, 最終更新日: 2023-08-16)

主引用文献

Fitzgerald, C.E.,Patel, S.B.,Becker, J.W.,Cameron, P.M.,Zaller, D.,Pikounis, V.B.,O'Keefe, S.J.,Scapin, G.
Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity
Nat.Struct.Biol., 10:764-769, 2003

PubMed Abstract: The quinazolinone and pyridol-pyrimidine classes of p38 MAP kinase inhibitors have a previously unseen degree of specificity for p38 over other MAP kinases. Comparison of the crystal structures of p38 bound to four different compounds shows that binding of the more specific molecules is characterized by a peptide flip between Met109 and Gly110. Gly110 is a residue specific to the alpha, beta and gamma isoforms of p38. The delta isoform and the other MAP kinases have bulkier residues in this position. These residues would likely make the peptide flip energetically unfavorable, thus explaining the selectivity of binding. To test this hypothesis, we constructed G110A and G110D mutants of p38 and measured the potency of several compounds against them. The results confirm that the selectivity of quinazolinones and pyridol-pyrimidines results from the presence of a glycine in position 110. This unique mode of binding may be exploited in the design of new p38 inhibitors.

PubMed: 12897767
DOI: 10.1038/nsb949

実験手法

X-RAY DIFFRACTION (2.5 Å)