3W8Q

Structure of the Human Mitogen-Activated Protein Kinase Kinase 1 (MEK1)

3W8Q の概要

• エントリーDOI: 10.2210/pdb3w8q/pdb
• 分子名称: Dual specificity mitogen-activated protein kinase kinase 1, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER (3 entities in total)
• 機能のキーワード: transferase, nucleotide-binding, phosphorylation
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: Q02750
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39760.38

構造登録者

Nakae, S.,Kitamura, M.,Shirai, T.,Tada, T. (登録日: 2013-03-20, 公開日: 2014-03-26, 最終更新日: 2024-05-29)

主引用文献

Nakae, S.,Kitamura, M.,Fujiwara, D.,Sawa, M.,Shirai, T.,Fujii, I.,Tada, T.
Structure of mitogen-activated protein kinase kinase 1 in the DFG-out conformation.
Acta Crystallogr.,Sect.F, 77:459-464, 2021

PubMed Abstract: Eukaryotic protein kinases contain an Asp-Phe-Gly (DFG) motif, the conformation of which is involved in controlling the catalytic activity, at the N-terminus of the activation segment. The motif can be switched between active-state (DFG-in) and inactive-state (DFG-out) conformations: however, the mechanism of conformational change is poorly understood, partly because there are few reports of the DFG-out conformation. Here, a novel crystal structure of nonphosphorylated human mitogen-activated protein kinase kinase 1 (MEK1; amino acids 38-381) complexed with ATP-γS is reported in which MEK1 adopts the DFG-out conformation. The crystal structure revealed that the structural elements (the αC helix and HRD motif) surrounding the active site are involved in the formation/stabilization of the DFG-out conformation. The ATP-γS molecule was bound to the canonical ATP-binding site in a different binding mode that has never been found in previously determined crystal structures of MEK1. This novel ATP-γS binding mode provides a starting point for the design of high-affinity inhibitors of nonphosphorylated inactive MEK1 that adopts the DFG-out conformation.

PubMed: 34866601
DOI: 10.1107/S2053230X21011687

実験手法

X-RAY DIFFRACTION (2.2 Å)