Structural insights into molecular-targeting helix-loop-helix peptide against vascular endothelial growth factor-A.

Autor: Michigami M; Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, 599-8531, Japan., Notsu K; Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, 599-8531, Japan., Kamo M; MARUWA Foods and Biosciences Inc., 170-1, Tsutsui-cho, Yamatokooriyama, Nara, 639-1123, Japan., Hirokawa T; National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan; Division of Biomedical Science, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan; Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 14, Ibaraki, 305-8575, Japan., Kinoshita T; Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, 599-8531, Japan., Inaka K; MARUWA Foods and Biosciences Inc., 170-1, Tsutsui-cho, Yamatokooriyama, Nara, 639-1123, Japan., Nakase I; Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, 599-8531, Japan., Fujii I; Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, 599-8531, Japan. Electronic address: fujii@omu.ac.jp.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Nov 19; Vol. 734, pp. 150749. Date of Electronic Publication: 2024 Sep 27.
DOI: 10.1016/j.bbrc.2024.150749
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Co-authors MK and KI are employees of MARUWA Foods and Biosciences, Inc.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: