PDBsum entry 4p0c

Protein binding

PDB id: 4p0c

Contents

Protein chain

88 a.a.

Ligands

SCN

Metals

_CL ×2

Waters ×141

PDB id:

4p0c

Name:

Protein binding

Title:

Crystal structure of nherf2 pdz1 domain in complex with lpa2

Structure:

Na(+)/h(+) exchange regulatory cofactor nhe- rf2/lysophosphatidic acid receptor 2 chimeric protein. Chain: a. Fragment: unp q15599 residues 9-90. Unp q9hbw0 residues 347-351. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.34Å R-factor: 0.147 R-free: 0.177

Authors:

J.Holcomb,Y.Jiang,G.Lu,L.Trescott,J.Brunzelle,N.Sirinupong,C.Li, A.Naren,Z.Yang

Key ref:

J.Holcomb et al. (2014). Structural insights into PDZ-mediated interaction of NHERF2 and LPA(2), a cellular event implicated in CFTR channel regulation. Biochem Biophys Res Commun, 446, 399-403. PubMed id: 24613836 DOI: 10.1016/j.bbrc.2014.02.128

Date:

20-Feb-14 Release date: 21-May-14

Protein chain

Q15599  (NHRF2_HUMAN) -  Na(+)/H(+) exchange regulatory cofactor NHE-RF2 from Homo sapiens

Seq: 337 a.a.

Struc: 88 a.a.*

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

DOI no: 10.1016/j.bbrc.2014.02.128

Biochem Biophys Res Commun 446:399-403 (2014)

PubMed id: 24613836

Structural insights into PDZ-mediated interaction of NHERF2 and LPA(2), a cellular event implicated in CFTR channel regulation.

J.Holcomb, Y.Jiang, G.Lu, L.Trescott, J.Brunzelle, N.Sirinupong, C.Li, A.P.Naren, Z.Yang.

ABSTRACT

The formation of CFTR-NHERF2-LPA2 macromolecular complex in airway epithelia regulates CFTR channel function and plays an important role in compartmentalized cAMP signaling. We previously have shown that disruption of the PDZ-mediated NHERF2-LPA2 interaction abolishes the LPA inhibitory effect and augments CFTR Cl(-) channel activity in vitro and in vivo. Here we report the first crystal structure of the NHERF2 PDZ1 domain in complex with the C-terminal LPA2 sequence. The structure reveals that the PDZ1-LPA2 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four LPA2 residues contributing to specific interactions. Comparison of the PDZ1-LPA2 structure to the structure of PDZ1 in complex with a different peptide provides insights into the diverse nature of PDZ1 substrate recognition and suggests that the conformational flexibility in the ligand binding pocket is involved in determining the broad substrate specificity of PDZ1. In addition, the structure reveals a small surface pocket adjacent to the ligand-binding site, which may have therapeutic implications. This study provides an understanding of the structural basis for the PDZ-mediated NHERF2-LPA2 interaction that could prove valuable in selective drug design against CFTR-related human diseases.