6OPI

phosphorylated ERK2 with SCH-CPD336

6OPI の概要

• エントリーDOI: 10.2210/pdb6opi/pdb
• 分子名称: Mitogen-activated protein kinase 1, (3R)-N-[3-(2-cyclopropylpyridin-4-yl)-1H-indazol-5-yl]-3-(methoxymethyl)-1-(2-oxo-2-{4-[4-(pyrimidin-2-yl)phenyl]-3,6-dihydropyridin-1(2H)-yl}ethyl)pyrrolidine-3-carboxamide (3 entities in total)
• 機能のキーワード: erk 2, mitogen activated protein kinase 2, map kinase 2, signaling protein, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41802.82

構造登録者

Vigers, G.P.,Smith, D. (登録日: 2019-04-25, 公開日: 2019-07-31, 最終更新日: 2024-10-23)

主引用文献

Pegram, L.M.,Liddle, J.C.,Xiao, Y.,Hoh, M.,Rudolph, J.,Iverson, D.B.,Vigers, G.P.,Smith, D.,Zhang, H.,Wang, W.,Moffat, J.G.,Ahn, N.G.
Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2.
Proc.Natl.Acad.Sci.USA, 116:15463-15468, 2019

PubMed Abstract: Conformational selection by small molecules expands inhibitory possibilities for protein kinases. Nuclear magnetic resonance (NMR) measurements of the mitogen-activated protein (MAP) kinase ERK2 have shown that activation by dual phosphorylation induces global motions involving exchange between two states, L and R. We show that ERK inhibitors Vertex-11e and SCH772984 exploit the small energetic difference between L and R to shift the equilibrium in opposing directions. An X-ray structure of active 2P-ERK2 complexed with AMP-PNP reveals a shift in the Gly-rich loop along with domain closure to position the nucleotide in a more catalytically productive conformation relative to inactive 0P-ERK2:ATP. X-ray structures of 2P-ERK2 complexed with Vertex-11e or GDC-0994 recapitulate this closure, which is blocked in a complex with a SCH772984 analog. Thus, the L→R shift in 2P-ERK2 is associated with movements needed to form a competent active site. Solution measurements by hydrogen-exchange mass spectrometry (HX-MS) reveal distinct binding interactions for Vertex-11e, GDC-0994, and AMP-PNP with active vs. inactive ERK2, where the extent of HX protection correlates with R state formation. Furthermore, Vertex-11e and SCH772984 show opposite effects on HX near the activation loop. Consequently, these inhibitors differentially affect MAP kinase phosphatase activity toward 2P-ERK2. We conclude that global motions in ERK2 reflect conformational changes at the active site that promote productive nucleotide binding and couple with changes at the activation loop to allow control of dephosphorylation by conformationally selective inhibitors.

PubMed: 31311868
DOI: 10.1073/pnas.1906824116

実験手法

X-RAY DIFFRACTION (3 Å)