9NC2

Structure of HPK1 with compound C3

9NC2 の概要

• エントリーDOI: 10.2210/pdb9nc2/pdb
• 関連するPDBエントリー: 9N48 9N4U 9N7R 9N9X 9NAC 9NBS 9NBX
• 分子名称: Mitogen-activated protein kinase kinase kinase kinase 1, N-{2-(3,3-difluoropyrrolidin-1-yl)-6-[(3R)-pyrrolidin-3-yl]pyrimidin-4-yl}-1-(propan-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: kinase, cancer, inhibitor, hdx, molecular dynamics, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71197.12

構造登録者

Kiefer, J.R.,Walters, B.T.,Wang, W.,Wu, P.,Duo, Y. (登録日: 2025-02-14, 公開日: 2025-06-25, 最終更新日: 2025-07-02)

主引用文献

Walters, B.T.,Patapoff, A.W.,Kiefer, J.R.,Wu, P.,Wang, W.
Integrating Hydrogen Exchange with Molecular Dynamics for Improved Ligand Binding Predictions.
J.Chem.Inf.Model., 65:6144-6154, 2025

PubMed Abstract: We introduce hydrogen-exchange experimental structure prediction (HX-ESP), a method that integrates hydrogen exchange (HX) data with molecular dynamics (MD) simulations to accurately predict ligand binding modes, even for targets requiring significant conformational changes. Benchmarking HX-ESP by fitting two ligands to PAK1 and four ligands to MAP4K1 (HPK1) and comparing the results to X-ray crystallography structures, demonstrates that HX-ESP can identify binding modes across a range of affinities significantly outperforming flexible docking for ligands necessitating large conformational adjustments. By objectively guiding simulations with experimental HX data, HX-ESP overcomes the long time scales required for binding predictions using traditional MD. This advancement enhances the accuracy of computational modeling in drug discovery and thus will accelerate the development of effective therapeutics.

PubMed: 40495786
DOI: 10.1021/acs.jcim.5c00397

実験手法

X-RAY DIFFRACTION (1.5 Å)