3N8M

Crystal Structure of the Grb2 SH2 Domain in Complex with An Acyclic Ligand Having the Sequence pYVNVP

Summary for 3N8M

• Entry DOI: 10.2210/pdb3n8m/pdb
• Related: 1BMB 1JYR 1TZE
• Descriptor: Growth factor receptor-bound protein 2, PEPTIDE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: grb2 sh2 domain, ligand preorganization, macrocycles, macrocyclic ligands, protein binding-peptide complex, protein binding/peptide
• Biological source: Homo sapiens (human)
• Cellular location: Golgi apparatus (By similarity): P62993
• Total number of polymer chains: 2
• Total formula weight: 14632.47

Authors

Whiddon, B.B.,Clements, J.H.,Martin, S.F. (deposition date: 2010-05-28, release date: 2010-12-15, Last modification date: 2023-11-22)

Primary citation

Delorbe, J.E.,Clements, J.H.,Whiddon, B.B.,Martin, S.F.
Thermodynamic and Structural Effects of Macrocyclization as a Constraining Method in Protein-Ligand Interactions.
ACS MED.CHEM.LETT., 1:448-452, 2010

PubMed Abstract: The thermodynamic and structural effects of macrocyclization as a tactic for stabilizing the biologically-active conformation of Grb2 SH2 binding peptides were investigated using isothermal titration calorimetry and x-ray crystallography. 23-Membered macrocycles containing the sequence pYVN were slightly more potent than their linear controls; however, preorganization did not necessarily eventuate in a more favorable binding entropy. Structures of complexes of macrocycle 7 and its acyclic control 8 are similar except for differences in relative orientations of corresponding atoms in the linking moieties of 7 and 8. There are no differences in the number of direct or water-mediated protein-ligand contacts that might account for the less favorable binding enthalpy of 7; however, an intramolecular hydrogen bond between the pY and pY+3 residues in 8 that is absent in 7 may be a factor. These studies highlight the difficulties associated with correlating energetics and structure in protein-ligand interactions.

PubMed: 21116482
DOI: 10.1021/ml100142y

Experimental method

X-RAY DIFFRACTION (2 Å)