PDBsum entry 5fi0

Protein binding

PDB id: 5fi0

Contents

Protein chains

344 a.a.

176 a.a.

Ligands

PO4 ×4

PDB id:

5fi0

Name:

Protein binding

Title:

Crystal structure of the p-rex1 dh/ph tandem in complex with rac1

Structure:

Phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 1 protein,phosphatidylinositol 3,4,5-trisphosphate- dependent rac exchanger 1 protein. Chain: a, c, e, g. Synonym: ptdins(3,4,5)-dependent rac exchanger 1,ptdins(3,4,5)- dependent rac exchanger 1. Engineered: yes. Ras-related c3 botulinum toxin substrate 1. Chain: b, d, f, h.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: prex1, kiaa1415. Expressed in: escherichia coli. Expression_system_taxid: 469008. Gene: rac1, tc25, mig5.

Resolution:

3.28Å R-factor: 0.192 R-free: 0.236

Authors:

J.N.Cash,J.J.G.Tesmer

Key ref:

J.N.Cash et al. (2016). 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. PubMed id: 27150042 DOI: 10.1016/j.str.2016.02.022

Date:

22-Dec-15 Release date: 20-Apr-16

Protein chains

Q8TCU6  (PREX1_HUMAN) -  Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein from Homo sapiens

Seq: 1659 a.a.

Struc: 344 a.a.*

Protein chains

P63000  (RAC1_HUMAN) -  Ras-related C3 botulinum toxin substrate 1 from Homo sapiens

Seq: 192 a.a.

Struc: 176 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains B, D, F, H: E.C.3.6.5.2 - small monomeric GTPase.
• Reaction: GTP + H2O = GDP + phosphate + H⁺

GTP + H2O = GDP + phosphate + H(+) (Bound ligand (Het Group name = PO4) corresponds exactly)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.str.2016.02.022

Structure 24:730-740 (2016)

PubMed id: 27150042

Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3.

J.N.Cash, E.M.Davis, J.J.Tesmer.

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.