5G4N

Crystal structure of the p53 cancer mutant Y220C in complex with a difluorinated derivative of the small molecule stabilizer Phikan083

Summary for 5G4N

• Entry DOI: 10.2210/pdb5g4n/pdb
• Related: 5G4M 5G4O
• Descriptor: CELLULAR TUMOR ANTIGEN P53, ZINC ION, 1-[9-(2,2-difluoroethyl)-9H-carbazol-3-yl]-N-methylmethanamine, ... (5 entities in total)
• Functional Keywords: transcription, p53, cancer, tumor suppression, dna binding, cancer therapy, small-molecule stabilizers, molecular chaperone, fluorine-protein interactions
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 49833.15

Authors

Joerger, A.C.,Bauer, M.,Jones, R.N.,Spencer, J. (deposition date: 2016-05-13, release date: 2016-06-22, Last modification date: 2024-01-10)

Primary citation

Bauer, M.R.,Jones, R.N.,Baud, M.G.J.,Wilcken, R.,Boeckler, F.M.,Fersht, A.R.,Joerger, A.C.,Spencer, J.
Harnessing Fluorine-Sulfur Contacts and Multipolar Interactions for the Design of P53 Mutant Y220C Rescue Drugs.
Acs Chem.Biol., 11:2265-, 2016

PubMed Abstract: Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-molecule stabilizers of this mutant. One of these molecules, PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with a KD = 150 μM, thereby increasing the melting temperature of the protein and slowing its rate of aggregation. Incorporation of fluorine atoms into small molecule ligands can substantially improve binding affinity to their protein targets. We have, therefore, harnessed fluorine-protein interactions to improve the affinity of this ligand. Step-wise introduction of fluorines at the carbazole ethyl anchor, which is deeply buried within the binding site in the Y220C-PhiKan083 complex, led to a 5-fold increase in affinity for a 2,2,2-trifluoroethyl anchor (ligand efficiency of 0.3 kcal mol(-1) atom(-1)). High-resolution crystal structures of the Y220C-ligand complexes combined with quantum chemical calculations revealed favorable interactions of the fluorines with protein backbone carbonyl groups (Leu145 and Trp146) and the sulfur of Cys220 at the mutation site. Affinity gains were, however, only achieved upon trifluorination, despite favorable interactions of the mono- and difluorinated anchors with the binding pocket, indicating a trade-off between energetically favorable protein-fluorine interactions and increased desolvation penalties. Taken together, the optimized carbazole scaffold provides a promising starting point for the development of high-affinity ligands to reactivate the tumor suppressor function of the p53 mutant Y220C in cancer cells.

PubMed: 27267810
DOI: 10.1021/ACSCHEMBIO.6B00315

Experimental method

X-RAY DIFFRACTION (1.35 Å)