9JU1

Helix-loop-helix peptide (VS42-LR3) in complex with VEGF-A

Summary for 9JU1

• Entry DOI: 10.2210/pdb9ju1/pdb
• Descriptor: VS42-LR3, Vascular endothelial growth factor A, long form, SULFATE ION, ... (4 entities in total)
• Functional Keywords: helix-loop-helix, inhibitor, complex, de novo protein, immune system-de novo protein complex, immune system/de novo protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 16784.15

Authors

Kamo, M.,Michigami, M.,Inaka, K.,Furubayashi, N.,Kaito, S.,Kobayashi, Y.,Shinohara, Y.,Fujii, I. (deposition date: 2024-10-07, release date: 2024-12-25)

Primary citation

Michigami, M.,Notsu, K.,Kamo, M.,Hirokawa, T.,Kinoshita, T.,Inaka, K.,Nakase, I.,Fujii, I.
Structural insights into molecular-targeting helix-loop-helix peptide against vascular endothelial growth factor-A.
Biochem Biophys Res Commun, 734:150749-, 2024

PubMed Abstract: Mid-sized binding peptides have recently emerged as a new therapeutic modality. A helix-loop-helix (HLH) peptide was designed as a scaffold for combinatorial peptide libraries. We screened the HLH peptide libraries against human vascular endothelial growth factor-A (VEGF) to generate a peptide, VS42-LR3, which inhibited VEGF/receptor interaction and suppressed tumor growth in a murine xenograft model of human colorectal cancer. Here, we report the first crystal structure of the HLH peptide in a complex with VEGF at high resolution using space-grown protein crystals. The X-ray structural analysis revealed that the monomeric VS42-LR3 adopted an HLH structure and bound to VEGF at the VEGF receptor-binding site. Interestingly, from the site-directed mutagenesis, thermodynamic analysis, and molecular dynamic simulations, it turned out that the loop region in the non-interacting surface to VEGF affected the structural rigidity of the whole HLH to increase the binding affinity. These findings provide valuable insights for the design of more structurally stable and higher affinity mid-sized binding peptides as well as HLH peptides, that could play a crucial role in advancing molecular-targeting therapies.

PubMed: 39357335
DOI: 10.1016/j.bbrc.2024.150749

Experimental method

X-RAY DIFFRACTION (1.45 Å)