5J2V

Crystal Structure of Hsp90-alpha Apo N-domain

Summary for 5J2V

• Entry DOI: 10.2210/pdb5j2v/pdb
• Descriptor: Heat shock protein HSP 90-alpha (2 entities in total)
• Functional Keywords: apo structure, chaperone
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 23205.30

Authors

Amaral, M.,Matias, P. (deposition date: 2016-03-30, release date: 2017-10-11, Last modification date: 2024-05-08)

Primary citation

Amaral, M.,Kokh, D.B.,Bomke, J.,Wegener, A.,Buchstaller, H.P.,Eggenweiler, H.M.,Matias, P.,Sirrenberg, C.,Wade, R.C.,Frech, M.
Protein conformational flexibility modulates kinetics and thermodynamics of drug binding.
Nat Commun, 8:2276-2276, 2017

PubMed Abstract: Structure-based drug design has often been restricted by the rather static picture of protein-ligand complexes presented by crystal structures, despite the widely accepted importance of protein flexibility in biomolecular recognition. Here we report a detailed experimental and computational study of the drug target, human heat shock protein 90, to explore the contribution of protein dynamics to the binding thermodynamics and kinetics of drug-like compounds. We observe that their binding properties depend on whether the protein has a loop or a helical conformation in the binding site of the ligand-bound state. Compounds bound to the helical conformation display slow association and dissociation rates, high-affinity and high cellular efficacy, and predominantly entropically driven binding. An important entropic contribution comes from the greater flexibility of the helical relative to the loop conformation in the ligand-bound state. This unusual mechanism suggests increasing target flexibility in the bound state by ligand design as a new strategy for drug discovery.

PubMed: 29273709
DOI: 10.1038/s41467-017-02258-w

Experimental method

X-RAY DIFFRACTION (1.59 Å)