7A00
Crystal structure of Shank1 PDZ in complex with L6F mutant of the C-terminal hexapeptide from GKAP
Summary for 7A00
| Entry DOI | 10.2210/pdb7a00/pdb |
| Descriptor | SH3 and multiple ankyrin repeat domains protein 1, L6F mutant of C-terminal hexapeptide from Guanylate kinase-associated protein (3 entities in total) |
| Functional Keywords | shank1 pdz, gkap, peptide binding protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 26238.26 |
| Authors | Zsofia, H.,Hetherington, K.,Fruzsina, H.,Edwards, T.A.,Wilson, A.J. (deposition date: 2020-08-05, release date: 2021-07-07, Last modification date: 2024-11-06) |
| Primary citation | Celis, S.,Hobor, F.,James, T.,Bartlett, G.J.,Ibarra, A.A.,Shoemark, D.K.,Hegedus, Z.,Hetherington, K.,Woolfson, D.N.,Sessions, R.B.,Edwards, T.A.,Andrews, D.M.,Nelson, A.,Wilson, A.J. Query-guided protein-protein interaction inhibitor discovery. Chem Sci, 12:4753-4762, 2021 Cited by PubMed Abstract: Protein-protein interactions (PPIs) are central to biological mechanisms, and can serve as compelling targets for drug discovery. Yet, the discovery of small molecule inhibitors of PPIs remains challenging given the large and typically shallow topography of the interacting protein surfaces. Here, we describe a general approach to the discovery of orthosteric PPI inhibitors that mimic specific secondary protein structures. Initially, hot residues at protein-protein interfaces are identified or from experimental data, and incorporated into secondary structure-based queries. Virtual libraries of small molecules are then shape-matched against the queries, and promising ligands docked to target proteins. The approach is exemplified experimentally using two unrelated PPIs that are mediated by an α-helix (p53/DM2) and a β-strand (GKAP/SHANK1-PDZ). In each case, selective PPI inhibitors are discovered with low μM activity as determined by a combination of fluorescence anisotropy and H-N HSQC experiments. In addition, hit expansion yields a series of PPI inhibitors with defined structure-activity relationships. It is envisaged that the generality of the approach will enable discovery of inhibitors of a wide range of unrelated secondary structure-mediated PPIs. PubMed: 34163731DOI: 10.1039/d1sc00023c PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.78 Å) |
Structure validation
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