8PFE

Crystal Structure of an Hexavariant of the b1 Domain of Human Neuropilin-1 in Complex with the KDKPPR Peptide

これはPDB形式変換不可エントリーです。

8PFE の概要

• エントリーDOI: 10.2210/pdb8pfe/pdb
• 分子名称: Neuropilin-1, LYS-ASP-LYS-PRO-PRO-ARG, ACETATE ION, ... (4 entities in total)
• 機能のキーワード: neuropilin-1, human, blood coagulation factors, cell adhesion, binding sites, protein binding
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 42134.86

構造登録者

Jelsch, C.,Favier, F.,Didierjean, C. (登録日: 2023-06-15, 公開日: 2023-08-02, 最終更新日: 2024-11-20)

主引用文献

Goudiaby, I.,Malliavin, T.E.,Mocchetti, E.,Mathiot, S.,Acherar, S.,Frochot, C.,Barberi-Heyob, M.,Guillot, B.,Favier, F.,Didierjean, C.,Jelsch, C.
New Crystal Form of Human Neuropilin-1 b1 Fragment with Six Electrostatic Mutations Complexed with KDKPPR Peptide Ligand.
Molecules, 28:-, 2023

PubMed Abstract: Neuropilin 1 (NRP1), a cell-surface co-receptor of a number of growth factors and other signaling molecules, has long been the focus of attention due to its association with the development and the progression of several types of cancer. For example, the KDKPPR peptide has recently been combined with a photosensitizer and a contrast agent to bind NRP1 for the detection and treatment by photodynamic therapy of glioblastoma, an aggressive brain cancer. The main therapeutic target is a pocket of the fragment b1 of NRP1 (NRP1-b1), in which vascular endothelial growth factors (VEGFs) bind. In the crystal packing of native human NRP1-b1, the VEGF-binding site is obstructed by a crystallographic symmetry neighbor protein, which prevents the binding of ligands. Six charged amino acids located at the protein surface were mutated to allow the protein to form a new crystal packing. The structure of the mutated fragment b1 complexed with the KDKPPR peptide was determined by X-ray crystallography. The variant crystallized in a new crystal form with the VEGF-binding cleft exposed to the solvent and, as expected, filled by the C-terminal moiety of the peptide. The atomic interactions were analyzed using new approaches based on a multipolar electron density model. Among other things, these methods indicated the role played by Asp320 and Glu348 in the electrostatic steering of the ligand in its binding site. Molecular dynamics simulations were carried out to further analyze the peptide binding and motion of the wild-type and mutant proteins. The simulations revealed that specific loops interacting with the peptide exhibited mobility in both the unbound and bound forms.

PubMed: 37513474
DOI: 10.3390/molecules28145603

実験手法

X-RAY DIFFRACTION (1.35 Å)