EMD-6457
Cryo-EM of CHIKV VLP in complex with Fab fragment of neutralizing antibody IM-CKV063
EMD-6457
Single-particle11.2 Å
Deposition: 04/09/2015Map released: 13/01/2016
Last modified: 13/01/2016
Sample Organism:
Chikungunya virus,
Mus musculus
Sample: Chikungunya (S27) virus-like particle in complex with Fab fragment of neutralizing antibody IM-CKV063
Deposition Authors: Jin J
,
Liss N,
Chen D-H,
Liao M,
Fox JM ,
Shimak RM,
Fong RH,
Chafets D,
Bakkour S,
Keating S ,
Fomin ME,
Muench MO ,
Sherman MB,
Doranz BJ,
Diamond MS,
Simmons G
Sample: Chikungunya (S27) virus-like particle in complex with Fab fragment of neutralizing antibody IM-CKV063
Deposition Authors: Jin J
,
Liss N,
Chen D-H,
Liao M,
Fox JM ,
Shimak RM,
Fong RH,
Chafets D,
Bakkour S,
Keating S ,
Fomin ME,
Muench MO ,
Sherman MB,
Doranz BJ,
Diamond MS,
Simmons G
Neutralizing Monoclonal Antibodies Block Chikungunya Virus Entry and Release by Targeting an Epitope Critical to Viral Pathogenesis
Jin J ,
Liss NM,
Chen DH,
Liao M,
Fox JM ,
Shimak RM,
Fong RH,
Chafets D,
Bakkour S,
Keating S ,
Fomin ME,
Muench MO ,
Sherman MB,
Doranz BJ,
Diamond MS,
Simmons G
(2015) Cell Rep. , 13 , 2553 - 2564
,
Liss NM,
Chen DH,
Liao M,
Fox JM ,
Shimak RM,
Fong RH,
Chafets D,
Bakkour S,
Keating S ,
Fomin ME,
Muench MO ,
Sherman MB,
Doranz BJ,
Diamond MS,
Simmons G
(2015) Cell Rep. , 13 , 2553 - 2564
Abstract:
We evaluated the mechanism by which neutralizing human monoclonal antibodies inhibit chikungunya virus (CHIKV) infection. Potently neutralizing antibodies (NAbs) blocked infection at multiple steps of the virus life cycle, including entry and release. Cryo-electron microscopy structures of Fab fragments of two human NAbs and chikungunya virus-like particles showed a binding footprint that spanned independent domains on neighboring E2 subunits within one viral spike, suggesting a mechanism for inhibiting low-pH-dependent membrane fusion. Detailed epitope mapping identified amino acid E2-W64 as a critical interaction residue. An escape mutation (E2-W64G) at this residue rendered CHIKV attenuated in mice. Consistent with these data, CHIKV-E2-W64G failed to emerge in vivo under the selection pressure of one of the NAbs, IM-CKV063. As our study suggests that antibodies engaging the residue E2-W64 can potently inhibit CHIKV at multiple stages of infection, antibody-based therapies or immunogens that target this region might have protective value.
We evaluated the mechanism by which neutralizing human monoclonal antibodies inhibit chikungunya virus (CHIKV) infection. Potently neutralizing antibodies (NAbs) blocked infection at multiple steps of the virus life cycle, including entry and release. Cryo-electron microscopy structures of Fab fragments of two human NAbs and chikungunya virus-like particles showed a binding footprint that spanned independent domains on neighboring E2 subunits within one viral spike, suggesting a mechanism for inhibiting low-pH-dependent membrane fusion. Detailed epitope mapping identified amino acid E2-W64 as a critical interaction residue. An escape mutation (E2-W64G) at this residue rendered CHIKV attenuated in mice. Consistent with these data, CHIKV-E2-W64G failed to emerge in vivo under the selection pressure of one of the NAbs, IM-CKV063. As our study suggests that antibodies engaging the residue E2-W64 can potently inhibit CHIKV at multiple stages of infection, antibody-based therapies or immunogens that target this region might have protective value.