5LRL

CRYSTAL STRUCTURE OF HSP90 IN COMPLEX WITH A003492875

Summary for 5LRL

• Entry DOI: 10.2210/pdb5lrl/pdb
• Descriptor: Heat shock protein HSP 90-alpha, 2-azanyl-5-chloranyl-~{N}-[(9~{R})-4-(1~{H}-imidazo[4,5-c]pyridin-2-yl)-9~{H}-fluoren-9-yl]pyrimidine-4-carboxamide (3 entities in total)
• Functional Keywords: chaperone protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 23758.32

Authors

Vallee, F.,Dupuy, A. (deposition date: 2016-08-19, release date: 2017-08-23, Last modification date: 2024-01-10)

Primary citation

Wolf, S.,Amaral, M.,Lowinski, M.,Vallee, F.,Musil, D.,Guldenhaupt, J.,Dreyer, M.K.,Bomke, J.,Frech, M.,Schlitter, J.,Gerwert, K.
Estimation of Protein-Ligand Unbinding Kinetics Using Non-Equilibrium Targeted Molecular Dynamics Simulations.
J.Chem.Inf.Model., 59:5135-5147, 2019

PubMed Abstract: We here report on nonequilibrium targeted molecular dynamics simulations as a tool for the estimation of protein-ligand unbinding kinetics. Correlating simulations with experimental data from SPR kinetics measurements and X-ray crystallography on two small molecule compound libraries bound to the N-terminal domain of the chaperone Hsp90, we show that the mean nonequilibrium work computed in an ensemble of trajectories of enforced ligand unbinding is a promising predictor for ligand unbinding rates. We furthermore investigate the molecular basis determining unbinding rates within the compound libraries. We propose ligand conformational changes and protein-ligand nonbonded interactions to impact on unbinding rates. Ligands may remain longer at the protein if they exhibit strong electrostatic and/or van der Waals interactions with the target. In the case of ligands with a rigid chemical scaffold that exhibit longer residence times, transient electrostatic interactions with the protein appear to facilitate unbinding. Our results imply that understanding the unbinding pathway and the protein-ligand interactions along this path is crucial for the prediction of small molecule ligands with defined unbinding kinetics.

PubMed: 31697501
DOI: 10.1021/acs.jcim.9b00592

Experimental method

X-RAY DIFFRACTION (1.33 Å)