8S0N

Crystal structure of the TMPRSS2 zymogen in complex with the nanobody A07

8S0N の概要

• エントリーDOI: 10.2210/pdb8s0n/pdb
• 関連するPDBエントリー: 8S0L 8S0M
• 分子名称: Transmembrane protease serine 2, nanobody A07 (3 entities in total)
• 機能のキーワード: protease, nanobody, inhibitor, zymogen, protein binding, protease-nanobody inhibitor complex, protease/nanobody inhibitor
• 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: 119907.91

構造登録者

Duquerroy, S.,Fernandez, I.,Rey, F. (登録日: 2024-02-14, 公開日: 2024-06-26, 最終更新日: 2024-11-06)

主引用文献

Fernandez, I.,Saunders, N.,Duquerroy, S.,Bolland, W.H.,Arbabian, A.,Baquero, E.,Blanc, C.,Lafaye, P.,Haouz, A.,Buchrieser, J.,Schwartz, O.,Rey, F.A.
Structural basis of TMPRSS2 zymogen activation and recognition by the HKU1 seasonal coronavirus.
Cell, 187:4246-4260.e16, 2024

PubMed Abstract: The human seasonal coronavirus HKU1-CoV, which causes common colds worldwide, relies on the sequential binding to surface glycans and transmembrane serine protease 2 (TMPRSS2) for entry into target cells. TMPRSS2 is synthesized as a zymogen that undergoes autolytic activation to process its substrates. Several respiratory viruses, in particular coronaviruses, use TMPRSS2 for proteolytic priming of their surface spike protein to drive membrane fusion upon receptor binding. We describe the crystal structure of the HKU1-CoV receptor binding domain in complex with TMPRSS2, showing that it recognizes residues lining the catalytic groove. Combined mutagenesis of interface residues and comparison across species highlight positions 417 and 469 as determinants of HKU1-CoV host tropism. The structure of a receptor-blocking nanobody in complex with zymogen or activated TMPRSS2 further provides the structural basis of TMPRSS2 activating conformational change, which alters loops recognized by HKU1-CoV and dramatically increases binding affinity.

PubMed: 38964326
DOI: 10.1016/j.cell.2024.06.007

実験手法

X-RAY DIFFRACTION (2.3 Å)