Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ.
Modular PDZ domains, found in many cell junction-associated proteins, mediate the clustering of membrane ion channels by binding to their C-terminus. The X-ray crystallographic structures of the third PDZ domain from the synaptic protein PSD-95 in complex with and in the absence of its peptide ligand have been determined at 1.8 angstroms and 2.3 angstroms resolution, respectively. The structures reveal that a four-residue C-terminal stretch (X-Thr/Ser-X-Val-COO(-)) engages the PDZ domain through antiparallel main chain interactions with a beta sheet of the domain. Recognition of the terminal carboxylate group of the peptide is conferred by a cradle of main chain amides provided by a Gly-Leu-Gly-Phe loop as well as by an arginine side chain. Specific side chain interactions and a prominent hydrophobic pocket explain the selective recognition of the C-terminal consensus sequence.
Doyle
D A
DA
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, NY 10021, USA.
Lee
A
A
Lewis
J
J
Kim
E
E
Sheng
M
M
MacKinnon
R
R
D003461:Crystallography; D007091:Image Processing, Computer-Assisted; D008565:Membrane Proteins / Q000737:chemistry*; D008967:Molecular Biology; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C033652:postsynaptic density proteins