5D3V

Crystal Structure of the P-Rex1 PH domain with Citrate Bound

Summary for 5D3V

• Entry DOI: 10.2210/pdb5d3v/pdb
• Related: 5D27 5D3W 5D3X 5D3Z
• Descriptor: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein, CITRATE ANION (3 entities in total)
• Functional Keywords: pleckstrin homology domain, beta sandwich, phosphatidylinositol-binding, lipid binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 38763.01

Authors

Cash, J.N.,Tesmer, J.J.G. (deposition date: 2015-08-06, release date: 2016-04-20, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.852 Å)