4UE1

Structure of the stapled peptide YS-01 bound to MDM2

Summary for 4UE1

• Entry DOI: 10.2210/pdb4ue1/pdb
• Related: 4UD7
• Descriptor: E3 UBIQUITIN-PROTEIN LIGASE MDM2, YS-01 (3 entities in total)
• Functional Keywords: ligase-peptide complex, ligase/peptide
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 8
• Total formula weight: 58619.08

Authors

Tan, Y.S.,Reeks, J.,Brown, C.J.,Jennings, C.E.,Eapen, R.S.,Tng, Q.S.,Thean, D.,Ying, Y.T.,Gago, F.J.F.,Lane, D.P.,Noble, M.E.M.,Verma, C. (deposition date: 2014-12-14, release date: 2016-01-13, Last modification date: 2023-12-20)

Primary citation

Tan, Y.S.,Reeks, J.,Brown, C.J.,Thean, D.,Ferrer Gago, F.J.,Yuen, T.Y.,Goh, E.T.,Lee, X.E.,Jennings, C.E.,Joseph, T.L.,Lakshminarayanan, R.,Lane, D.P.,Noble, M.E.,Verma, C.S.
Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design.
J Phys Chem Lett, 7:3452-3457, 2016

PubMed Abstract: Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successful at reproducing experimental structural data, their ability to predict new binding sites that are yet to be identified and characterized has not been demonstrated. Here, we report the use of benzenes as probe molecules in ligand-mapping MD (LMMD) simulations to predict the existence of two novel binding sites on the surface of the oncoprotein MDM2. One of them was serendipitously confirmed by biophysical assays and X-ray crystallography to be important for the binding of a new family of hydrocarbon stapled peptides that were specifically designed to target the other putative site. These results highlight the predictive power of LMMD and suggest that predictions derived from LMMD simulations can serve as a reliable basis for the identification of novel ligand binding sites in structure-based drug design.

PubMed: 27532490
DOI: 10.1021/acs.jpclett.6b01525

Experimental method

X-RAY DIFFRACTION (1.45 Å)