8W4F

SARS-CoV-2 spike protein in complex with a trivalent nanobody

8W4F の概要

• エントリーDOI: 10.2210/pdb8w4f/pdb
• EMDBエントリー: 36904
• 分子名称: Spike glycoprotein, Tribody (2 entities in total)
• 機能のキーワード: trivalent nanobody, viral neutralization, all-rbd-down spike, viral protein, viral protein-immune system complex, viral protein/immune system
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2; 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 434314.86

構造登録者

Jiang, X.Y.,Qian, J.Q.,Zhu, H.X.,Qin, Q.,Huang, Q. (登録日: 2023-08-24, 公開日: 2024-07-24, 最終更新日: 2024-11-20)

主引用文献

Jiang, X.,Qin, Q.,Zhu, H.,Qian, J.,Huang, Q.
Structure-guided design of a trivalent nanobody cluster targeting SARS-CoV-2 spike protein.
Int.J.Biol.Macromol., 256:128191-128191, 2024

PubMed Abstract: Nanobodies are natural anti-SARS-CoV-2 drug candidates. Engineering multivalent nanobodies is an effective way to improve the functional binding affinity of natural nanobodies by simultaneously targeting multiple sites on viral proteins. However, multivalent nanobodies have usually been engineered by trial and error, and rational designs are still lacking. Here, we describe a structure-guided design of a self-assembled trivalent nanobody cluster targeting the SARS-CoV-2 spike protein. Using the nanobody Nb6 as a monovalent binder, we first selected a human-derived trimerization scaffold evaluated by molecular dynamics simulations, then selected an optimal linker according to the minimum distance between Nb6 and the trimerization scaffold, and finally successfully engineered a trivalent nanobody cluster called Tribody. Compared with the low-affinity monovalent counterpart (Nb6), Tribody showed much higher target binding affinity (K < 1 pM) and thus had a 900-fold increase in antiviral neutralization against SARS-CoV-2 pseudovirus. We determined the cryo-EM structure of the Tribody-spike complex and confirmed that all three Nb6 binders of Tribody collectively bind to the three receptor-binding domains (RBDs) of the spike and lock them in a 3-RBD-down conformation, fully consistent with our structure-guided design. This study demonstrates that synthetic nanobody clusters with human-derived self-assembled scaffolds are potential protein drugs against SARS-CoV-2 coronaviruses.

PubMed: 38000614
DOI: 10.1016/j.ijbiomac.2023.128191

実験手法

ELECTRON MICROSCOPY (4.2 Å)