5D3Y: Crystal Structure Of The P-rex1 Ph Domain With Inositol-(1,3,4,5)- Tetrakisphosphate Bound

Citation:
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 Gbetagamma 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.
PDB ID: 5D3YDownload
MMDB ID: 138713
PDB Deposition Date: 2015/8/6
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 1.95  Å
Source Organism:
Similar Structures:
Biological Unit for 5D3Y: monomeric; determined by author and by software (PISA)
Molecular Components in 5D3Y
Label Count Molecule
Protein (1 molecule)
1
Phosphatidylinositol 3,4,5-trisphosphate-dependent RAC Exchanger 1 Protein(Gene symbol: PREX1)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.