Revisiting a challenging p53 binding site: a diversity-optimized HEFLib reveals diverse binding modes in T-p53C-Y220C
Jason Stahlecker, Theresa Klett, Martin Schwer, Simon Jaag, Marcel Dammann, Larissa N. Ernst, Michael B. Braun, Markus O. Zimmermann, Markus Krämer, Michael Lämmerhofer, Thilo Stehle, M.P. Coles, Frank M. Boeckler
Abstract
N-HSQC NMR. We could identify four hits binding in the Y220C cleft, one hit binding covalently and four hits binding to an uncharacterized binding site. Compound 1151 could be crystallized showing a flip of C220 and thus opening subsite 3. Additionally, 4482 was identified to alkylate cysteines. Data shows that the diversity-optimized HEFLib leads to multiple diverse hits. The identified scaffolds can be used to further optimize interactions with T-p53C-Y220C and increase thermal stability.
Topics & Concepts
DruggabilityHeteronuclear single quantum coherence spectroscopyComputational biologyBinding sitePlasma protein bindingCombinatorial chemistryChemistryStereochemistryBiochemistryBiophysicsBiologyTwo-dimensional nuclear magnetic resonance spectroscopyGeneCancer-related Molecular PathwaysRNA modifications and cancerEnzyme Structure and Function