4QDR

Physical basis for Nrp2 ligand binding

4QDR の概要

• エントリーDOI: 10.2210/pdb4qdr/pdb
• 関連するPDBエントリー: 4QDQ 4QDS
• 分子名称: Neuropilin-2 (2 entities in total)
• 機能のキーワード: coagulation factor domain, discoidin domain, receptor, vegf-c, membrane, cell adhesion
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein. Isoform s9: Secreted : O60462
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36599.21

構造登録者

Parker, M.W.,Vander Kooi, C.W. (登録日: 2014-05-14, 公開日: 2015-04-15, 最終更新日: 2024-10-30)

主引用文献

Parker, M.W.,Linkugel, A.D.,Goel, H.L.,Wu, T.,Mercurio, A.M.,Vander Kooi, C.W.
Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form.
Structure, 23:677-687, 2015

PubMed Abstract: Vascular endothelial growth factor C (VEGF-C) is a potent lymphangiogenic cytokine that signals via the coordinated action of two cell surface receptors, Neuropilin-2 (Nrp2) and VEGFR-3. Diseases associated with both loss and gain of VEGF-C function, lymphedema and cancer, respectively, motivate studies of VEGF-C/Nrp2 binding and inhibition. Here, we demonstrate that VEGF-C binding to Nrp2 is regulated by C-terminal proteolytic maturation. The structure of the VEGF-C C terminus in complex with the ligand binding domains of Nrp2 demonstrates that a cryptic Nrp2 binding motif is released upon proteolysis, allowing specific engagement with the b1 domain of Nrp2. Based on the identified structural requirements for Nrp2 binding to VEGF-C, we hypothesized that the endogenous secreted splice form of Nrp2, s9Nrp2, may function as a selective inhibitor of VEGF-C. We find that s9Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and cellular signaling. These data provide critical insight into VEGF-C/Nrp2 binding and inhibition.

PubMed: 25752543
DOI: 10.1016/j.str.2015.01.018

実験手法

X-RAY DIFFRACTION (2.4 Å)