5OU8

Crystal structure of Glycoprotein VI in complex with collagen-peptide (GPO)5

5OU8 の概要

• エントリーDOI: 10.2210/pdb5ou8/pdb
• 関連するPDBエントリー: 5OU7
• 分子名称: Platelet glycoprotein VI, (GPO)5, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: platelet, glycoprotein, gpvi, collagen-binding, platelet activation, gpo5, crp, blood clotting
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 44403.47

構造登録者

Feitsma, L.J.,Huizinga, E.G. (登録日: 2017-08-23, 公開日: 2018-09-05, 最終更新日: 2024-01-17)

主引用文献

Feitsma, L.J.,Brondijk, H.C.,Jarvis, G.E.,Hagemans, D.,Bihan, D.,Jerah, N.,Versteeg, M.,Farndale, R.W.,Huizinga, E.G.
Structural insights into collagen binding by platelet receptor glycoprotein VI.
Blood, 139:3087-3098, 2022

PubMed Abstract: Glycoprotein VI (GPVI) mediates collagen-induced platelet activation after vascular damage and is an important contributor to the onset of thrombosis, heart attack, and stroke. Animal models of thrombosis have identified GPVI as a promising target for antithrombotic therapy. Although for many years the crystal structure of GPVI has been known, the essential details of its interaction with collagen have remained elusive. Here, we present crystal structures of the GPVI ectodomain bound to triple-helical collagen peptides, which reveal a collagen-binding site across the β-sheet of the D1 domain. Mutagenesis and binding studies confirm the observed binding site and identify Trp76, Arg38, and Glu40 as essential residues for binding to fibrillar collagens and collagen-related peptides (CRPs). GPVI binds a site on collagen comprising two collagen chains with the core formed by the sequence motif OGPOGP. Potent GPVI-binding peptides from Toolkit-III all contain OGPOGP; weaker binding peptides frequently contain a partial motif varying at either terminus. Alanine-scanning of peptide III-30 also identified two AGPOGP motifs that contribute to GPVI binding, but steric hindrance between GPVI molecules restricts the maximum binding capacity. We further show that no cooperative interactions could occur between two GPVI monomers binding to a stretch of (GPO)5 and that binding of ≥2 GPVI molecules to a fibril-embedded helix requires non-overlapping OGPOGP motifs. Our structure confirms the previously suggested similarity in collagen binding between GPVI and leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) but also indicates significant differences that may be exploited for the development of receptor-specific therapeutics.

PubMed: 35245360
DOI: 10.1182/blood.2021013614

実験手法

X-RAY DIFFRACTION (2.5 Å)