4L67

Crystal Structure of Catalytic Domain of PAK4

4L67 の概要

• エントリーDOI: 10.2210/pdb4l67/pdb
• 分子名称: Serine/threonine-protein kinase PAK 4 (3 entities in total)
• 機能のキーワード: catalytic domain of pak4, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm: O96013 O96013
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 35906.71

構造登録者

Wang, W.,Song, J. (登録日: 2013-06-12, 公開日: 2013-08-14, 最終更新日: 2024-10-30)

主引用文献

Wang, W.,Lim, L.,Baskaran, Y.,Manser, E.,Song, J.
NMR binding and crystal structure reveal that intrinsically-unstructured regulatory domain auto-inhibits PAK4 by a mechanism different for that of PAK1
Biochem.Biophys.Res.Commun., 438:169-174, 2013

PubMed Abstract: Six human PAK members are classified into groups I (PAKs 1-3) and II (PAK4-6). Previously, only group I PAKs were thought to be auto-inhibited but very recently PAK4, the prototype of group II PAKs, has also been shown to be auto-inhibited by its N-terminal regulatory domain. However, the complete auto-inhibitory domain (AID) sequence remains undefined and the mechanism underlying its auto-inhibition is largely elusive. Here, the N-terminal regulatory domain of PAK4 sufficient for auto-inhibiting and binding Cdc42/Rac was characterized to be intrinsically unstructured, but nevertheless we identified the entire AID sequence by NMR. Strikingly, an AID peptide was derived by deleting the binding-unnecessary residues, which has a Kd of 320 nM to the PAK4 catalytic domain. Consequently, the PAK4 crystal structure complexed with the entire AID has been determined, which reveals that the complete kinase cleft is occupied by 20 AID residuescomposed of an N-terminal α-helix and a previously-identified pseudosubstrate motif, thus achieving auto-inhibition. Our study reveals that PAK4 is auto-inhibited by a novel mechanism which is completely different from that for PAK1, thus bearing critical implications for design of inhibitors specific for group II PAKs.

PubMed: 23876315
DOI: 10.1016/j.bbrc.2013.07.047

実験手法

X-RAY DIFFRACTION (2.8 Å)