6WO2

Crystal Structure of the Grb2 SH2 Domain in Complex with a Tripeptide: Ac-pY-Ac6c-N-isohexyl

6WO2 の概要

• エントリーDOI: 10.2210/pdb6wo2/pdb
• 関連するPDBエントリー: 4P9V 6WM1
• 分子名称: Growth factor receptor-bound protein 2, ACE-PTR-02K-ASN-U67, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: grb2 sh2 ligand preorganization, peptide binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 28919.65

構造登録者

Martin, S.F.,Clements, J.H. (登録日: 2020-04-24, 公開日: 2020-09-02, 最終更新日: 2023-11-15)

主引用文献

Cramer, D.L.,Cheng, B.,Tian, J.,Clements, J.H.,Wypych, R.M.,Martin, S.F.
Some thermodynamic effects of varying nonpolar surfaces in protein-ligand interactions.
Eur.J.Med.Chem., 208:112771-112771, 2020

PubMed Abstract: Understanding how making structural changes in small molecules affects their binding affinities for targeted proteins is central to improving strategies for rational drug design. To assess the effects of varying the nature of nonpolar groups upon binding entropies and enthalpies, we designed and prepared a set of Grb2-SH2 domain ligands, Ac-pTyr-Acc-Asn-(CH)-R, in which the size and electrostatic nature of R groups at the pTyr+3 site were varied. The complexes of these ligands with the Grb2-SH2 domain were evaluated in a series of studies in which the binding thermodynamics were determined using isothermal titration calorimetry, and binding interactions were examined in crystallographic studies of two different complexes. Notably, adding nonpolar groups to the pTyr+3 site leads to higher binding affinities, but the magnitude and energetic origins of these effects vary with the nature of the R substituent. For example, enhancements to binding affinities using aliphatic R groups are driven by more favorable changes in binding entropies, whereas aryl R groups improve binding free energies through a combination of more favorable changes in binding enthalpies and entropies. However, enthalpy/entropy compensation plays a significant role in these associations and mitigates against any significant variation in binding free energies, which vary by only 0.8 kcal•mol, with changes in the electrostatic nature and size of the R group. Crystallographic studies show that differences in ΔG° or ΔH° correlate with buried nonpolar surface area, but they do not correlate with the total number of polar or van der Waals contacts. The relative number of ordered water molecules and relative order in the side chains at pTyr+3 correlate with differences in -TΔS°. Overall, these studies show that burial of nonpolar surface can lead to enhanced binding affinities arising from dominating entropy- or enthalpy-driven hydrophobic effects, depending upon the electrostatic nature of the apolar R group.

PubMed: 32916312
DOI: 10.1016/j.ejmech.2020.112771

実験手法

X-RAY DIFFRACTION (2 Å)