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PDBsum entry 4p0c
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Protein binding
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PDB id
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4p0c
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References listed in PDB file
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Key reference
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Title
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Structural insights into pdz-Mediated interaction of nherf2 and lpa(2), A cellular event implicated in cftr channel regulation.
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Authors
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J.Holcomb,
Y.Jiang,
G.Lu,
L.Trescott,
J.Brunzelle,
N.Sirinupong,
C.Li,
A.P.Naren,
Z.Yang.
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Ref.
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Biochem Biophys Res Commun, 2014,
446,
399-403.
[DOI no: ]
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PubMed id
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Abstract
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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.
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