8W4V

Crystal structure of human HSP90 in complex with compound 4

8W4V の概要

• エントリーDOI: 10.2210/pdb8w4v/pdb
• 分子名称: Heat shock protein HSP 90-alpha, MAGNESIUM ION, 4-[2-[(dimethylamino)methyl]phenyl]sulfanylbenzene-1,3-diol, ... (4 entities in total)
• 機能のキーワード: hsp90, atpase, ntd, complex, inhibitor, chaperone
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27637.23

構造登録者

Xu, C.,Zhang, X.L.,Bai, F. (登録日: 2023-08-25, 公開日: 2024-04-17, 最終更新日: 2024-05-08)

主引用文献

Xu, C.,Zhang, X.,Zhao, L.,Verkhivker, G.M.,Bai, F.
Accurate Characterization of Binding Kinetics and Allosteric Mechanisms for the HSP90 Chaperone Inhibitors Using AI-Augmented Integrative Biophysical Studies.
Jacs Au, 4:1632-1645, 2024

PubMed Abstract: The binding kinetics of drugs to their targets are gradually being recognized as a crucial indicator of the efficacy of drugs , leading to the development of various computational methods for predicting the binding kinetics in recent years. However, compared with the prediction of binding affinity, the underlying structure and dynamic determinants of binding kinetics are more complicated. Efficient and accurate methods for predicting binding kinetics are still lacking. In this study, quantitative structure-kinetics relationship (QSKR) models were developed using 132 inhibitors targeting the ATP binding domain of heat shock protein 90α (HSP90α) to predict the dissociation rate constant (), enabling a direct assessment of the drug-target residence time. These models demonstrated good predictive performance, where hydrophobic and hydrogen bond interactions significantly influence the prediction. In subsequent applications, our models were used to assist in the discovery of new inhibitors for the N-terminal domain of HSP90α (N-HSP90α), demonstrating predictive capabilities on an experimental validation set with a new scaffold. In X-ray crystallography experiments, the loop-middle conformation of N-HSP90α was observed for the first time (previously, the loop-middle conformation had only been observed in -N-HSP90α structures). Interestingly, we observed different conformations of N-HSP90α simultaneously in an asymmetric unit, which was also observed in a -N-HSP90α structure, suggesting an equilibrium of conformations between different states in solution, which could be one of the determinants affecting the binding kinetics of the ligand. Different ligands can undergo conformational selection or alter the equilibrium of conformations, inducing conformational rearrangements and resulting in different effects on binding kinetics. We then used molecular dynamics simulations to describe conformational changes of N-HSP90α in different conformational states. In summary, the study of the binding kinetics and molecular mechanisms of N-HSP90α provides valuable information for the development of more targeted therapeutic approaches.

PubMed: 38665669
DOI: 10.1021/jacsau.4c00123

実験手法

X-RAY DIFFRACTION (1.81 Å)