4P0C: Crystal Structure of NHERF2 PDZ1 Domain in Complex with LPA2

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.
PDB ID: 4P0CDownload
MMDB ID: 120129
PDB Deposition Date: 2014/2/20
Updated in MMDB: 2018/07
Experimental Method:
x-ray diffraction
Resolution: 1.339  Å
Source Organism:
Similar Structures:
Biological Unit for 4P0C: monomeric; determined by author and by software (PISA)
Molecular Components in 4P0C
Label Count Molecule
Protein (1 molecule)
Na(+)/h(+) Exchange Regulatory Cofactor Nhe-rf2/lysophosphatidic Acid Receptor 2 Chimeric Protein
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB