3S8L

Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing Hydrophobic Surface Area

Summary for 3S8L

• Entry DOI: 10.2210/pdb3s8l/pdb
• Related: 3OV1 3OVE 3S8N 3S8O
• Descriptor: Growth factor receptor-bound protein 2, pYAc4cN, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: grb2 sh2 domain, phosphotyrosine-containing tripeptide, signaling protein-antagonist complex, signaling protein/antagonist
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P62993
• Total number of polymer chains: 2
• Total formula weight: 14382.52

Authors

Clements, J.H.,Stephen, F.M. (deposition date: 2011-05-29, release date: 2011-11-02, Last modification date: 2024-11-20)

Primary citation

Myslinski, J.M.,Delorbe, J.E.,Clements, J.H.,Martin, S.F.
Protein-ligand interactions: thermodynamic effects associated with increasing nonpolar surface area.
J.Am.Chem.Soc., 133:18518-18521, 2011

PubMed Abstract: Thermodynamic parameters were determined for complex formation between the Grb2 SH2 domain and Ac-pTyr-Xaa-Asn derived tripeptides in which the Xaa residue is an α,α-cycloaliphatic amino acid that varies in ring size from three- to seven-membered. Although the six- and seven-membered ring analogs are approximately equipotent, binding affinities of those having three- to six-membered rings increase incrementally with ring size because increasingly more favorable binding enthalpies dominate increasingly less favorable binding entropies, a finding consistent with an enthalpy-driven hydrophobic effect. Crystallographic analysis reveals that the only significant differences in structures of the complexes are in the number of van der Waals contacts between the domain and the methylene groups in the Xaa residues. There is a positive correlation between buried nonpolar surface area and binding free energy and enthalpy, but not with ΔC(p). Displacing a water molecule from a protein-ligand interface is not necessarily reflected in a favorable change in binding entropy. These findings highlight some of the fallibilities associated with commonly held views of relationships of structure and energetics in protein-ligand interactions and have significant implications for ligand design.

PubMed: 22007755
DOI: 10.1021/ja2068752

Experimental method

X-RAY DIFFRACTION (1.71 Å)