PDBsum entry 3imd

Signaling protein/peptide

PDB id: 3imd

Contents

Protein chains

101 a.a. *

Ligands

FYQ ×2

Metals

_CL ×4

_MG

Waters ×191

* Residue conservation analysis

PDB id:

3imd

Name:

Signaling protein/peptide

Title:

Crystal structure of the grb2 sh2 domain in complex with a flexible ac-py-q-n-nh2 tripeptide mimic

Structure:

Growth factor receptor-bound protein 2. Chain: a, b. Fragment: sh2 domain. Synonym: adapter protein grb2, sh2/sh3 adapter grb2, protein ash. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: grb2, ash. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.00Å R-factor: 0.199 R-free: 0.237

Authors:

J.H.Clements

Key ref:

J.E.DeLorbe et al. (2009). Thermodynamic and structural effects of conformational constraints in protein-ligand interactions. Entropic paradoxy associated with ligand preorganization. J Am Chem Soc, 131, 16758-16770. PubMed id: 19886660

Date:

10-Aug-09 Release date: 17-Nov-09

Protein chains

P62993  (GRB2_HUMAN) -  Growth factor receptor-bound protein 2 from Homo sapiens

Seq: 217 a.a.

Struc: 101 a.a.

Enzyme reactions

• Enzyme class: E.C.?

J Am Chem Soc 131:16758-16770 (2009)

PubMed id: 19886660

Thermodynamic and structural effects of conformational constraints in protein-ligand interactions. Entropic paradoxy associated with ligand preorganization.

J.E.DeLorbe, J.H.Clements, M.G.Teresk, A.P.Benfield, H.R.Plake, L.E.Millspaugh, S.F.Martin.

ABSTRACT

Succinate- and cyclopropane-derived phosphotyrosine (pY) replacements were incorporated into a series of Grb2 SH2 binding ligands wherein the pY+1 residue was varied to determine explicitly how variations in ligand preorganization affect binding energetics and structure. The complexes of these ligands with the Grb2 SH2 domain were examined in a series of thermodynamic and structural investigations using isothermal titration calorimetry and X-ray crystallography. The binding enthalpies for all ligands were favorable, and although binding entropies for all ligands having a hydrophobic residue at the pY+1 site were favorable, binding entropies for those having a hydrophilic residue at this site were unfavorable. Preorganized ligands generally bound with more favorable Gibbs energies than their flexible controls, but this increased affinity was the consequence of relatively more favorable binding enthalpies. Unexpectedly, binding entropies of the constrained ligands were uniformly disfavored relative to their flexible controls, demonstrating that the widely held belief that ligand preorganization should result in an entropic advantage is not necessarily true. Crystallographic studies of complexes of several flexible and constrained ligands having the same amino acid at the pY+1 position revealed extensive similarities, but there were some notable differences. There are a greater number of direct polar contacts in complexes of the constrained ligands that correlate qualitatively with their more favorable binding enthalpies and Gibbs energies. There are more single water-mediated contacts between the domain and the flexible ligand of each pair; although fixing water molecules at a protein-ligand interface is commonly viewed as entropically unfavorable, entropies for forming these complexes are favored relative to those of their constrained counterparts. Crystallographic b-factors in the complexes of constrained ligands are greater than those of their flexible counterparts, an observation that seems inconsistent with our finding that entropies for forming complexes of flexible ligands are relatively more favorable. This systematic study highlights the profound challenges and complexities associated with predicting how structural changes in a ligand will affect enthalpies, entropies, and structure in protein-ligand interactions.