9O8W

Crystal structure of an MKP5 mutant, Y435F, in complex with an allosteric inhibitor

9O8W の概要

• エントリーDOI: 10.2210/pdb9o8w/pdb
• 分子名称: Dual specificity protein phosphatase 10, 3,3-dimethyl-1-{[9-(methylsulfanyl)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl]sulfanyl}butan-2-one, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: mkp5, allosteric inhibitor, allosteric site, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 105289.54

構造登録者

Manjula, R.,Bennett, A.M.,Lolis, E. (登録日: 2025-04-16, 公開日: 2025-07-30, 最終更新日: 2025-08-13)

主引用文献

Skeens, E.,Maschietto, F.,Manjula, R.,Shillingford, S.,Murphy, J.,Lolis, E.J.,Batista, V.S.,Bennett, A.M.,Lisi, G.P.
Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase.
Nat Commun, 16:7011-7011, 2025

PubMed Abstract: Dual-specificity mitogen-activated protein kinase (MAPK) phosphatases (MKPs) directly dephosphorylate and inactivate the MAPKs. Although the catalytic mechanism of dephosphorylation of the MAPKs by the MKPs is established, a complete molecular picture of the regulatory interplay between the MAPKs and MKPs still remains to be fully explored. Here, we sought to define the molecular mechanism of MKP5 regulation through an allosteric site within its catalytic domain. We demonstrate using crystallographic and NMR spectroscopy approaches that residue Y435 is required to maintain the structural integrity of the allosteric pocket. Along with molecular dynamics simulations, these data provide insight into how changes in the allosteric pocket propagate conformational flexibility in the surrounding loops to reorganize catalytically crucial residues in the active site. Furthermore, Y435 is required for the interaction with p38 MAPK and JNK, thereby promoting dephosphorylation. Collectively, these results demonstrate critical roles for the allosteric site in coordinating both MKP5 catalysis and MAPK binding.

PubMed: 40745179
DOI: 10.1038/s41467-025-62150-w

実験手法

X-RAY DIFFRACTION (2.39 Å)