PDBsum entry 5d3x

Lipid binding protein

PDB id: 5d3x

Contents

Protein chains

151 a.a.

141 a.a.

Ligands

4IP ×2

Waters ×222

PDB id:

5d3x

Name:

Lipid binding protein

Title:

Crystal structure of the p-rex1 ph domain with inositol-(1,3,4,5)- tetrakisphosphate bound

Structure:

Phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 1 protein. Chain: a, b. Fragment: unp residues 245-408. Synonym: ptdins(3,4,5)-dependent rac exchanger 1. Engineered: yes. Other_details: pleckstrin homology domain

Source:

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

Resolution:

1.69Å R-factor: 0.178 R-free: 0.214

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:

06-Aug-15 Release date: 20-Apr-16

Protein chain

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

Seq: 1659 a.a.

Struc: 151 a.a.*

Protein chain

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

Seq: 1659 a.a.

Struc: 141 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

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.