Structure of severe acute respiratory syndrome coronavirus receptor-binding domain complexed with neutralizing antibody.
Identifieur interne : 003C90 ( Main/Exploration ); précédent : 003C89; suivant : 003C91Structure of severe acute respiratory syndrome coronavirus receptor-binding domain complexed with neutralizing antibody.
Auteurs : Ponraj Prabakaran [États-Unis] ; Jianhua Gan ; Yang Feng ; Zhongyu Zhu ; Vidita Choudhry ; Xiaodong Xiao ; Xinhua Ji ; Dimiter S. DimitrovSource :
- The Journal of biological chemistry [ 0021-9258 ] ; 2006.
Descripteurs français
- KwdFr :
- Anticorps antiviraux (immunologie), Cristallisation, Données de séquences moléculaires, Humains, Modèles moléculaires, Récepteurs viraux (), Récepteurs viraux (immunologie), Récepteurs viraux (métabolisme), Résonance plasmonique de surface, Similitude de séquences d'acides aminés, Séquence d'acides aminés, Tests de neutralisation, Virus du SRAS (métabolisme).
- MESH :
- immunologie : Anticorps antiviraux, Récepteurs viraux.
- métabolisme : Récepteurs viraux, Virus du SRAS.
- Cristallisation, Données de séquences moléculaires, Humains, Modèles moléculaires, Récepteurs viraux, Résonance plasmonique de surface, Similitude de séquences d'acides aminés, Séquence d'acides aminés, Tests de neutralisation.
English descriptors
- KwdEn :
- Amino Acid Sequence, Antibodies, Viral (immunology), Crystallization, Humans, Models, Molecular, Molecular Sequence Data, Neutralization Tests, Receptors, Virus (chemistry), Receptors, Virus (immunology), Receptors, Virus (metabolism), SARS Virus (metabolism), Sequence Homology, Amino Acid, Surface Plasmon Resonance.
- MESH :
- chemical , chemistry : Receptors, Virus.
- chemical , immunology : Antibodies, Viral, Receptors, Virus.
- chemical , metabolism : Receptors, Virus.
- metabolism : SARS Virus.
- Amino Acid Sequence, Crystallization, Humans, Models, Molecular, Molecular Sequence Data, Neutralization Tests, Sequence Homology, Amino Acid, Surface Plasmon Resonance.
Abstract
The severe acute respiratory syndrome coronavirus (SARS-CoV, or SCV), which caused a world-wide epidemic in 2002 and 2003, binds to a receptor, angiotensin-converting enzyme 2 (ACE2), through the receptor-binding domain (RBD) of its envelope (spike, S) glycoprotein. The RBD is very immunogenic; it is a major SCV neutralization determinant and can elicit potent neutralizing antibodies capable of out-competing ACE2. However, the structural basis of RBD immunogenicity, RBD-mediated neutralization, and the role of RBD in entry steps following its binding to ACE2 have not been elucidated. By mimicking immune responses with the use of RBD as an antigen to screen a large human antibody library derived from healthy volunteers, we identified a novel potent cross-reactive SCV-neutralizing monoclonal antibody, m396, which competes with ACE2 for binding to RBD, and determined the crystal structure of the RBD-antibody complex at 2.3-A resolution. The antibody-bound RBD structure is completely defined, revealing two previously unresolved segments (residues 376-381 and 503-512) and a new disulfide bond (between residues 378 and 511). Interestingly, the overall structure of the m396-bound RBD is not significantly different from that of the ACE2-bound RBD. The antibody epitope is dominated by a 10-residue-long protruding beta6-beta7 loop with two putative ACE2-binding hotspot residues (Ile-489 and Tyr-491). These results provide a structural rationale for the function of a major determinant of SCV immunogenicity and neutralization, the development of SCV therapeutics based on the antibody paratope and epitope, and a retrovaccinology approach for the design of anti-SCV vaccines. The available structural information indicates that the SCV entry may not be mediated by ACE2-induced conformational changes in the RBD but may involve other conformational changes or/and yet to be identified coreceptors.
DOI: 10.1074/jbc.M600697200
PubMed: 16597622
Affiliations:
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Le document en format XML
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<author><name sortKey="Zhu, Zhongyu" sort="Zhu, Zhongyu" uniqKey="Zhu Z" first="Zhongyu" last="Zhu">Zhongyu Zhu</name>
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<term>Antibodies, Viral (immunology)</term>
<term>Crystallization</term>
<term>Humans</term>
<term>Models, Molecular</term>
<term>Molecular Sequence Data</term>
<term>Neutralization Tests</term>
<term>Receptors, Virus (chemistry)</term>
<term>Receptors, Virus (immunology)</term>
<term>Receptors, Virus (metabolism)</term>
<term>SARS Virus (metabolism)</term>
<term>Sequence Homology, Amino Acid</term>
<term>Surface Plasmon Resonance</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Anticorps antiviraux (immunologie)</term>
<term>Cristallisation</term>
<term>Données de séquences moléculaires</term>
<term>Humains</term>
<term>Modèles moléculaires</term>
<term>Récepteurs viraux ()</term>
<term>Récepteurs viraux (immunologie)</term>
<term>Récepteurs viraux (métabolisme)</term>
<term>Résonance plasmonique de surface</term>
<term>Similitude de séquences d'acides aminés</term>
<term>Séquence d'acides aminés</term>
<term>Tests de neutralisation</term>
<term>Virus du SRAS (métabolisme)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Receptors, Virus</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Antibodies, Viral</term>
<term>Receptors, Virus</term>
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<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Receptors, Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Anticorps antiviraux</term>
<term>Récepteurs viraux</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Récepteurs viraux</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term>
<term>Crystallization</term>
<term>Humans</term>
<term>Models, Molecular</term>
<term>Molecular Sequence Data</term>
<term>Neutralization Tests</term>
<term>Sequence Homology, Amino Acid</term>
<term>Surface Plasmon Resonance</term>
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<term>Données de séquences moléculaires</term>
<term>Humains</term>
<term>Modèles moléculaires</term>
<term>Récepteurs viraux</term>
<term>Résonance plasmonique de surface</term>
<term>Similitude de séquences d'acides aminés</term>
<term>Séquence d'acides aminés</term>
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<front><div type="abstract" xml:lang="en">The severe acute respiratory syndrome coronavirus (SARS-CoV, or SCV), which caused a world-wide epidemic in 2002 and 2003, binds to a receptor, angiotensin-converting enzyme 2 (ACE2), through the receptor-binding domain (RBD) of its envelope (spike, S) glycoprotein. The RBD is very immunogenic; it is a major SCV neutralization determinant and can elicit potent neutralizing antibodies capable of out-competing ACE2. However, the structural basis of RBD immunogenicity, RBD-mediated neutralization, and the role of RBD in entry steps following its binding to ACE2 have not been elucidated. By mimicking immune responses with the use of RBD as an antigen to screen a large human antibody library derived from healthy volunteers, we identified a novel potent cross-reactive SCV-neutralizing monoclonal antibody, m396, which competes with ACE2 for binding to RBD, and determined the crystal structure of the RBD-antibody complex at 2.3-A resolution. The antibody-bound RBD structure is completely defined, revealing two previously unresolved segments (residues 376-381 and 503-512) and a new disulfide bond (between residues 378 and 511). Interestingly, the overall structure of the m396-bound RBD is not significantly different from that of the ACE2-bound RBD. The antibody epitope is dominated by a 10-residue-long protruding beta6-beta7 loop with two putative ACE2-binding hotspot residues (Ile-489 and Tyr-491). These results provide a structural rationale for the function of a major determinant of SCV immunogenicity and neutralization, the development of SCV therapeutics based on the antibody paratope and epitope, and a retrovaccinology approach for the design of anti-SCV vaccines. The available structural information indicates that the SCV entry may not be mediated by ACE2-induced conformational changes in the RBD but may involve other conformational changes or/and yet to be identified coreceptors.</div>
</front>
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<name sortKey="Dimitrov, Dimiter S" sort="Dimitrov, Dimiter S" uniqKey="Dimitrov D" first="Dimiter S" last="Dimitrov">Dimiter S. Dimitrov</name>
<name sortKey="Feng, Yang" sort="Feng, Yang" uniqKey="Feng Y" first="Yang" last="Feng">Yang Feng</name>
<name sortKey="Gan, Jianhua" sort="Gan, Jianhua" uniqKey="Gan J" first="Jianhua" last="Gan">Jianhua Gan</name>
<name sortKey="Ji, Xinhua" sort="Ji, Xinhua" uniqKey="Ji X" first="Xinhua" last="Ji">Xinhua Ji</name>
<name sortKey="Xiao, Xiaodong" sort="Xiao, Xiaodong" uniqKey="Xiao X" first="Xiaodong" last="Xiao">Xiaodong Xiao</name>
<name sortKey="Zhu, Zhongyu" sort="Zhu, Zhongyu" uniqKey="Zhu Z" first="Zhongyu" last="Zhu">Zhongyu Zhu</name>
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