EMD-28190
SARS-CoV-2 RBD in complex with biparatopic nanobody BP10 local refinement
EMD-28190
Single-particle3.89 Å
Deposition: 19/09/2022Map released: 28/12/2022
Last modified: 28/12/2022
Sample Organism:
Severe acute respiratory syndrome coronavirus 2,
Vicugna pacos
Sample: SARS-CoV-2 Spike in complex with biparatopic nanobody BP10
Deposition Authors: Pymm PG, Glukhova A
,
Tham WH
Sample: SARS-CoV-2 Spike in complex with biparatopic nanobody BP10
Deposition Authors: Pymm PG, Glukhova A
,
Tham WH
Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2.
Pymm P,
Redmond SJ,
Dolezal O ,
Mordant F ,
Lopez E ,
Cooney JP,
Davidson KC ,
Haycroft ER ,
Tan CW,
Seneviratna R,
Grimley SL,
Purcell DFJ,
Kent SJ,
Wheatley AK,
Wang LF,
Leis A,
Glukhova A ,
Pellegrini M ,
Chung AW ,
Subbarao K,
Uldrich AP,
Tham WH ,
Godfrey DI,
Gherardin NA
(2022) iScience , 25 , 105259 - 105259
,
Mordant F ,
Lopez E ,
Cooney JP,
Davidson KC ,
Haycroft ER ,
Tan CW,
Seneviratna R,
Grimley SL,
Purcell DFJ,
Kent SJ,
Wheatley AK,
Wang LF,
Leis A,
Glukhova A ,
Pellegrini M ,
Chung AW ,
Subbarao K,
Uldrich AP,
Tham WH ,
Godfrey DI,
Gherardin NA
(2022) iScience , 25 , 105259 - 105259
Abstract:
The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralizing capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralizers with enhanced ability to control viral escape mutants.
The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralizing capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralizers with enhanced ability to control viral escape mutants.