5FI1

Crystal Structure of the P-Rex1 DH/PH tandem in complex with Cdc42

5FI1 の概要

• エントリーDOI: 10.2210/pdb5fi1/pdb
• 関連するPDBエントリー: 5D27 5D3V 5D3W 5D3X 5D3Y 5FI0
• 分子名称: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein,Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein, Cell division control protein 42 homolog (2 entities in total)
• 機能のキーワード: dbl homology domain, pleckstrin homology domain, gtpase, rhogef, protein binding, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64683.53

構造登録者

Cash, J.N.,Tesmer, J.J.G. (登録日: 2015-12-22, 公開日: 2016-04-20, 最終更新日: 2023-09-27)

主引用文献

Cash, J.N.,Davis, E.M.,Tesmer, J.J.
Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3.
Structure, 24:730-740, 2016

PubMed Abstract: Phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger 1 (P-Rex1) is a Rho guanine nucleotide exchange factor synergistically activated by PIP3 and Gβγ that plays an important role in the metastasis of breast, prostate, and skin cancer, making it an attractive therapeutic target. However, the molecular mechanisms behind P-Rex1 regulation are poorly understood. We determined structures of the P-Rex1 pleckstrin homology (PH) domain bound to the headgroup of PIP3 and resolved that PIP3 binding to the PH domain is required for P-Rex1 activity in cells but not for membrane localization, which points to an allosteric activation mechanism by PIP3. We also determined structures of the P-Rex1 tandem Dbl homology/PH domains in complexes with two of its substrate GTPases, Rac1 and Cdc42. Collectively, this study provides important molecular insights into P-Rex1 regulation and tools for targeting the PIP3-binding pocket of P-Rex1 with a new generation of cancer chemotherapeutic agents.

PubMed: 27150042
DOI: 10.1016/j.str.2016.02.022

実験手法

X-RAY DIFFRACTION (3.203 Å)