6YX2

Crystal structure of SHANK1 PDZ in complex with a peptide-small molecule hybrid

Summary for 6YX2

• Entry DOI: 10.2210/pdb6yx2/pdb
• Related: 6YWZ 6YX0 6YX1
• Descriptor: SH3 and multiple ankyrin repeat domains protein 1, PWW-THR-ARG-LEU, 4-[[(~{E})-5-oxidanylidenepentanoyldiazenyl]methyl]benzoic acid, ... (4 entities in total)
• Functional Keywords: protein protein interactions, pdz domain hybrid structures, fragment-based drug discovery, beta-sheets, acylhydrazone, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 25986.03

Authors

Hegedus, Z.,Hobor, F.,Shoemark, D.K.,Celis, S.,Lian, L.J.,Trinh, C.H.,Sessions, R.B.,Edwards, T.A.,Wilson, A.J. (deposition date: 2020-04-30, release date: 2021-01-20, Last modification date: 2024-01-24)

Primary citation

Hegedus, Z.,Hobor, F.,Shoemark, D.K.,Celis, S.,Lian, L.Y.,Trinh, C.H.,Sessions, R.B.,Edwards, T.A.,Wilson, A.J.
Identification of beta-strand mediated protein-protein interaction inhibitors using ligand-directed fragment ligation.
Chem Sci, 12:2286-2293, 2021

PubMed Abstract: β-Strand mediated protein-protein interactions (PPIs) represent underexploited targets for chemical probe development despite representing a significant proportion of known and therapeutically relevant PPI targets. β-Strand mimicry is challenging given that both amino acid side-chains and backbone hydrogen-bonds are typically required for molecular recognition, yet these are oriented along perpendicular vectors. This paper describes an alternative approach, using GKAP/SHANK1 PDZ as a model and dynamic ligation screening to identify small-molecule replacements for tranches of peptide sequence. A peptide truncation of GKAP functionalized at the N- and C-termini with acylhydrazone groups was used as an anchor. Reversible acylhydrazone bond exchange with a library of aldehyde fragments in the presence of the protein as template and screening using a fluorescence anisotropy (FA) assay identified peptide hybrid hits with comparable affinity to the GKAP peptide binding sequence. Identified hits were validated using FA, ITC, NMR and X-ray crystallography to confirm selective inhibition of the target PDZ-mediated PPI and mode of binding. These analyses together with molecular dynamics simulations demonstrated the ligands make transient interactions with an unoccupied basic patch through electrostatic interactions, establishing proof-of-concept that this unbiased approach to ligand discovery represents a powerful addition to the armory of tools that can be used to identify PPI modulators.

PubMed: 34163995
DOI: 10.1039/d0sc05694d

Experimental method

X-RAY DIFFRACTION (1.62 Å)