Crystal structure of the Shank PDZ-ligand complex reveals a class I PDZ interaction and a novel PDZ-PDZ dimerization

J Biol Chem. 2003 Nov 28;278(48):48099-104. doi: 10.1074/jbc.M306919200. Epub 2003 Sep 3.


The Shank/proline-rich synapse-associated protein family of multidomain proteins is known to play an important role in the organization of synaptic multiprotein complexes. For instance, the Shank PDZ domain binds to the C termini of guanylate kinase-associated proteins, which in turn interact with the guanylate kinase domain of postsynaptic density-95 scaffolding proteins. Here we describe the crystal structures of Shank1 PDZ in its peptide free form and in complex with the C-terminal hexapeptide (EAQTRL) of guanylate kinase-associated protein (GKAP1a) determined at 1.8- and 2.25-A resolutions, respectively. The structure shows the typical class I PDZ interaction of PDZ-peptide complex with the consensus sequence -X-(Thr/Ser)-X-Leu. In addition, Asp-634 within the Shank1 PDZ domain recognizes the positively charged Arg at -1 position and hydrogen bonds, and salt bridges between Arg-607 and the side chains of the ligand at -3 and -5 positions contribute further to the recognition of the peptide ligand. Remarkably, whether free or complexed, Shank1 PDZ domains form dimers with a conserved beta B/beta C loop and N-terminal beta A strands, suggesting a novel model of PDZ-PDZ homodimerization. This implies that antiparallel dimerization through the N-terminal beta A strands could be a common configuration among PDZ dimers. Within the dimeric structure, the two-peptide binding sites are arranged so that the N termini of the bound peptide ligands are in close proximity and oriented toward the 2-fold axis of the dimer. This configuration may provide a means of facilitating dimeric organization of PDZ-target assemblies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • Aspartic Acid / chemistry
  • Carrier Proteins / chemistry*
  • Crystallography, X-Ray
  • Dimerization
  • Escherichia coli / metabolism
  • Hydrogen Bonding
  • Leucine / chemistry
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Nerve Tissue Proteins / chemistry*
  • Peptides / chemistry
  • Protein Binding
  • Protein Structure, Tertiary
  • Rats
  • Sequence Homology, Amino Acid


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Ligands
  • Nerve Tissue Proteins
  • Peptides
  • Shank1 protein, rat
  • postsynaptic density proteins
  • Aspartic Acid
  • Leucine

Associated data

  • PDB/1Q3O
  • PDB/1Q3P