PDBsum entry 1q3p

Peptide binding protein

PDB id: 1q3p

Contents

Protein chains

98 a.a. *

103 a.a. *

Ligands

GLU-ALA-GLN-THR-ARG-LEU ×2

Waters ×44

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Crystal structure of the shank pdz-Ligand complex reveals a class i pdz interaction and a novel pdz-Pdz dimerization.

Authors

Y.J.Im, J.H.Lee, S.H.Park, S.J.Park, S.H.Rho, G.B.Kang, E.Kim, S.H.Eom.

Ref.

J Biol Chem, 2003, 278, 48099-48104. [DOI no: 10.1074/jbc.M306919200]

PubMed id

12954649

Abstract

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.

Figure 1.
FIG. 1. Structure of the SHANK1 PDZ domain. A, stereoview of a ribbon diagram showing the monomeric structure of the Shank PDZ-ligand complex. The -strands are labeled A- F, and the -helices are labeled A and B. The ligand is colored dark gray. The dotted line indicates a disordered loop (residues 610-614) that is not seen in peptide-bound structure. All of the residues in the loop were observed in peptide-free structure. B, amino acid sequence alignment of the PDZ domains from the rat and human Shank family, human NHERF (37), rat PSD95 (26), and rat GRIP1 (35). The sequences were aligned using the program ClustalX (38). Highly conserved residues are shaded in black and gray. The secondary structure elements of Shank1 PDZ are shown as arrows ( -strands), bars ( -helices), and lines (connecting loops). C, superposition of the PDZ domains. Black ribbon indicates Shank1 PDZ domain. Light and dark gray ribbons indicate PDZ domains of human NHERF (Protein Data Bank code 1G9O [PDB] ) and rat PSD95 (Protein Data Bank code 1BFE [PDB] ), respectively.

Figure 3.
FIG. 3. Overall structures of the PDZ dimer. A, Shank1 PDZ dimer. The black arrow indicates the N-terminal end of each peptide ligand. B, ribbon diagram of the GRIP PDZ6 dimer (Protein Data Bank code 1N7F [PDB] ). C, Shank PDZ dimer interface. Side chains of hydrophobic residues at the interface are shown as ball and stick models. D, amino acid sequence and predicted secondary structure of the C-terminal domain of PIX. The secondary structure was predicted using the PredictProtein Web server (cubic.bioc.columbia.edu/predictprotein/). E, proposed model of the Shank1 PDZ and PIX C terminus complex. The figures were made using PyMOL (www.pymol.org).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 48099-48104) copyright 2003.