4p0c

Crystal Structure of NHERF2 PDZ1 Domain in Complex with LPA2

spinqualitylabelsall models 4p0c, resolution 1.34Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4p0c is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, SCN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NHRF2_HUMAN Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May also act as scaffold protein in the nucleus. Publication Abstract from PubMed 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. Structural insights into PDZ-mediated interaction of NHERF2 and LPA(2), a cellular event implicated in CFTR channel regulation.,Holcomb J, Jiang Y, Lu G, Trescott L, Brunzelle J, Sirinupong N, Li C, Naren AP, Yang Z Biochem Biophys Res Commun. 2014 Mar 28;446(1):399-403. doi:, 10.1016/j.bbrc.2014.02.128. Epub 2014 Mar 12. PMID:24613836 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Lysophosphatidic acid receptor

Proteopedia Page Contributors and Editors (what is this?)

OCA