9KKU

Helix-loop-helix peptide (M49) in complex with VEGF-A

Summary for 9KKU

• Entry DOI: 10.2210/pdb9kku/pdb
• Descriptor: Vascular endothelial growth factor A, long form, M49 (3 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: 4
• Total formula weight: 33284.67

Authors

Kamo, M.,Michigami, M.,Inaka, K.,Furubayashi, N.,Kaito, S.,Kobayashi, Y.,Shinohara, Y.,Fujii, I. (deposition date: 2024-11-14, release date: 2024-12-11)

Primary citation

Michigami, M.,Kira, R.,Kamo, M.,Hirokawa, T.,Kinoshita, T.,Inaka, K.,Nakase, I.,Fujii, I.
Structural Insights into Helix-Loop-Helix Peptides for "Ligand-Targeting" Intracellular Drug Delivery via VEGF Receptor-Mediated Endocytosis.
Biochem.Biophys.Res.Commun., 741:150980-150980, 2024

PubMed Abstract: As a new alternative to antibody-drug conjugates, we developed "ligand-targeting" peptide-drug conjugates (PDCs), in which conformationally constrained helix-loop-helix (HLH) peptide M49 targeting human vascular endothelial growth factor-A (VEGF) was used as a drug carrier. The biochemical study showed that HLH peptide M49 made a complex with VEGF in the extracellular environment, and then the M49/VEGF complex interacts with the receptor on the cell surface to induce cellular internalization via the endocytic pathway. Here, we present an X-ray crystal structure of the M49/VEGF complex at 1.5 Å resolution using a protein crystal grown in microgravity. The structure illustrated the "ligand-targeting" cellular uptake mechanism for intracellular drug delivery and the molecular basis on the peptide-VEGF binding mode with tight binding and high target specificity. In addition, mutational studies and thermodynamic analysis provided information on the driving forces of the complex formation. This work would contribute to the design of mid-size molecular-targeting peptides as well as HLH peptides, advancing the research in drug discovery and chemical biology.

PubMed: 39580956
DOI: 10.1016/j.bbrc.2024.150980

Experimental method

X-RAY DIFFRACTION (1.46 Å)