3ESK

Structure of HOP TPR2A domain in complex with the non-cognate Hsc70 peptide ligand

3ESK の概要

• エントリーDOI: 10.2210/pdb3esk/pdb
• 関連するPDBエントリー: 1ELR 1ELW
• 分子名称: Stress-induced-phosphoprotein 1, Heat shock cognate 71 kDa protein, NICKEL (II) ION, ... (4 entities in total)
• 機能のキーワード: tpr2a, hsp90, hsc70, tetratricopeptide repeat, nucleus, tpr repeat, chaperone, stress response
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cytoplasm (By similarity): P31948; Cytoplasm: P11142
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 16474.09

構造登録者

Kajander, T.,Regan, L. (登録日: 2008-10-06, 公開日: 2009-07-07, 最終更新日: 2023-09-06)

主引用文献

Kajander, T.,Sachs, J.N.,Goldman, A.,Regan, L.
Electrostatic interactions of Hsp-organizing protein tetratricopeptide domains with Hsp70 and Hsp90: computational analysis and protein engineering.
J.Biol.Chem., 284:25364-25374, 2009

PubMed Abstract: The Hsp-organizing protein (HOP) binds to the C termini of the chaperones Hsp70 and Hsp90, thus bringing them together so that substrate proteins can be passed from Hsp70 to Hsp90. Because Hsp90 is essential for the correct folding and maturation of many oncogenic proteins, it has become a significant target for anti-cancer drug design. HOP binds to Hsp70 and Hsp90 via two independent tetratricopeptide (TPR) domains, TPR1 and TPR2A, respectively. We have analyzed ligand binding using Poisson-Boltzmann continuum electrostatic calculations, free energy perturbation, molecular dynamics simulations, and site-directed mutagenesis to delineate the contribution of different interactions to the affinity and specificity of the TPR-peptide interactions. We found that continuum electrostatic calculations could be used to guide protein design by removing unfavorable interactions to increase binding affinity, with an 80-fold increase in affinity for TPR2A. Contributions at buried charged residues, however, were better predicted by free energy perturbation calculations. We suggest using a combination of the two approaches for increasing the accuracy of results, with free energy perturbation calculations used only at selected buried residues of the ligand binding pocket. Finally we present the crystal structure of TPR2A in complex with its non-cognate Hsp70 ligand, which provides insight on the origins of specificity in TPR domain-peptide recognition.

PubMed: 19586912
DOI: 10.1074/jbc.M109.033894

実験手法

X-RAY DIFFRACTION (2.05 Å)