3O5N

Tetrahydroquinoline carboxylates are potent inhibitors of the Shank PDZ domain, a putative target in autism disorders

Summary for 3O5N

• Entry DOI: 10.2210/pdb3o5n/pdb
• Descriptor: SH3 and multiple ankyrin repeat domains protein 3, (3aS,4R,9bR)-9-nitro-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-4,6-dicarboxylic acid (3 entities in total)
• Functional Keywords: pdz domain, protein-protein interaction, gkap, postsynaptic density, protein binding
• Biological source: Mus musculus (mouse)
• Cellular location: Cytoplasm: Q4ACU6
• Total number of polymer chains: 8
• Total formula weight: 97951.67

Authors

Saupe, J.,Roske, Y.,Schillinger, C.,Kamdem, N.,Radetzki, S.,Diehl, A.,Oschkinat, H.,Krause, G.,Heinemann, U.,Rademann, J. (deposition date: 2010-07-28, release date: 2011-06-15, Last modification date: 2024-02-21)

Primary citation

Saupe, J.,Roske, Y.,Schillinger, C.,Kamdem, N.,Radetzki, S.,Diehl, A.,Oschkinat, H.,Krause, G.,Heinemann, U.,Rademann, J.
Discovery, structure-activity relationship studies, and crystal structure of nonpeptide inhibitors bound to the shank3 PDZ domain.
Chemmedchem, 6:1411-1422, 2011

PubMed Abstract: Shank is the central scaffolding protein of the postsynaptic density (PSD) protein complex found in cells of the central nervous system. Cellular studies indicate a prominent role of the protein in the organization of the PSD, in the development of neuronal morphology, in neuronal signaling, and in synaptic plasticity, thus linking Shank functions to the molecular basis of learning and memory. Mutations in the Shank gene have been found in several neuronal disorders including mental retardation, typical autism, and Asperger syndrome. Shank is linked to the PSD complex via its PDZ domain that binds to the C-terminus of guanylate-kinase-associated protein (GKAP). Here, small-molecule inhibitors of Shank3 PDZ domain are developed. A fluorescence polarization assay based on an identified high-affinity peptide is established, and tetrahydroquinoline carboxylates are identified as inhibitors of this protein-protein interaction. Chemical synthesis via a hetero-Diels-Alder strategy is employed for hit optimization, and structure-activity relationship studies are performed. Best hits possess K(i) values in the 10 μM range, and binding to the PDZ domain is confirmed by ¹H,¹⁵N HSQC NMR experiments. One of the hits crystallizes with the Shank3 PDZ domain. The structure, analyzed at a resolution of 1.85 Å, reveals details of the binding mode. Finally, binding to PDZ domains of PSD-95, syntrophin, and DVL3 was studied using ¹H,¹⁵N HSQC NMR spectroscopy.

PubMed: 21626699
DOI: 10.1002/cmdc.201100094

Experimental method

X-RAY DIFFRACTION (1.83 Å)