6ZFL

High resolution structure of VEGF-A 12:107 crystallized in tetragonal form

Summary for 6ZFL

• Entry DOI: 10.2210/pdb6zfl/pdb
• Related: 6Z13 6Z3F 6ZBR 6ZCD
• Descriptor: Vascular endothelial growth factor A, (4S)-2-METHYL-2,4-PENTANEDIOL, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: growth factor, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 23277.67

Authors

Gaucher, J.-F.,Broussy, S.,Reille-Seroussi, M. (deposition date: 2020-06-17, release date: 2021-06-30, Last modification date: 2024-10-23)

Primary citation

Gaucher, J.F.,Reille-Seroussi, M.,Broussy, S.
Structural and ITC Characterization of Peptide-Protein Binding: Thermodynamic Consequences of Cyclization Constraints, a Case Study on Vascular Endothelial Growth Factor Ligands.
Chemistry, 2022

PubMed Abstract: Macrocyclization constraints are widely used in the design of protein ligands to stabilize their bioactive conformation and increase their affinities. However, the resulting changes in binding entropy can be puzzling and uncorrelated to affinity gains. Here, the thermodynamic (Isothermal Titration Calorimetry) and structural (X-ray, NMR and CD) analysis of a complete series of lactam-bridged peptide ligands of the vascular endothelial growth factor, and their unconstrained analogs are reported. It is shown that differences in thermodynamics arise mainly from the folding energy of the peptide upon binding. The systematic reduction in conformational entropy penalty due to helix pre-organization can be counterbalanced by an unfavorable vibrational entropy change if the constraints are too rigid. The gain in configurational entropy partially escapes the enthalpy/entropy compensation and leads to an improvement in affinity. The precision of the analytical ITC method makes this study a possible benchmark for constrained peptides optimization.

PubMed: 35665969
DOI: 10.1002/chem.202200465

Experimental method

X-RAY DIFFRACTION (1.6 Å)