A Virus-Binding Hot Spot on Human Angiotensin-Converting Enzyme 2 Is Critical for Binding of Two Different Coronaviruses▿
Identifieur interne : 002161 ( Main/Exploration ); précédent : 002160; suivant : 002162A Virus-Binding Hot Spot on Human Angiotensin-Converting Enzyme 2 Is Critical for Binding of Two Different Coronaviruses▿
Auteurs : Kailang Wu [États-Unis] ; Lang Chen [États-Unis] ; Guiqing Peng [États-Unis] ; Wenbo Zhou [États-Unis] ; Christopher A. Pennell [États-Unis] ; Louis M. Mansky [États-Unis] ; Robert J. Geraghty [États-Unis] ; Fang Li [États-Unis]Source :
- Journal of Virology [ 0022-538X ] ; 2011.
Descripteurs français
- KwdFr :
- Analyse de mutations d'ADN, Attachement viral, Coronavirus humain NL63 (physiologie), Humains, Liaison aux protéines, Peptidyl-Dipeptidase A (génétique), Peptidyl-Dipeptidase A (métabolisme), Récepteurs viraux (génétique), Récepteurs viraux (métabolisme), Transduction génétique, Virus du SRAS (physiologie).
- MESH :
- génétique : Peptidyl-Dipeptidase A, Récepteurs viraux.
- métabolisme : Peptidyl-Dipeptidase A, Récepteurs viraux.
- physiologie : Coronavirus humain NL63, Virus du SRAS.
- Analyse de mutations d'ADN, Attachement viral, Humains, Liaison aux protéines, Transduction génétique.
English descriptors
- KwdEn :
- MESH :
- chemical , genetics : Peptidyl-Dipeptidase A, Receptors, Virus.
- chemical , metabolism : Peptidyl-Dipeptidase A, Receptors, Virus.
- physiology : Coronavirus NL63, Human, SARS Virus.
- DNA Mutational Analysis, Humans, Protein Binding, Transduction, Genetic, Virus Attachment.
Abstract
How viruses evolve to select their receptor proteins for host cell entry is puzzling. We recently determined the crystal structures of NL63 coronavirus (NL63-CoV) and SARS coronavirus (SARS-CoV) receptor-binding domains (RBDs), each complexed with their common receptor, human angiotensin-converting enzyme 2 (hACE2), and proposed the existence of a virus-binding hot spot on hACE2. Here we investigated the function of this hypothetical hot spot using structure-guided biochemical and functional assays. The hot spot consists of a salt bridge surrounded by hydrophobic tunnel walls. Mutations that disturb the hot spot structure have significant effects on virus/receptor interactions, revealing critical energy contributions from the hot spot structure. The tunnel structure at the NL63-CoV/hACE2 interface is more compact than that at the SARS-CoV/hACE2 interface, and hence RBD/hACE2 binding affinities are decreased either by NL63-CoV mutations decreasing the tunnel space or by SARS-CoV mutations increasing the tunnel space. Furthermore, NL63-CoV RBD inhibits hACE2-dependent transduction by SARS-CoV spike protein, a successful application of the hot spot theory that has the potential to become a new antiviral strategy against SARS-CoV infections. These results suggest that the structural features of the hot spot on hACE2 were among the driving forces for the convergent evolution of NL63-CoV and SARS-CoV.
Url:
DOI: 10.1128/JVI.02274-10
PubMed: 21411533
PubMed Central: 3094985
Affiliations:
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Le document en format XML
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Pennell</name><affiliation wicri:level="2"><nlm:aff id="aff3">Cancer Center, Center for Immunology, University of Minnesota, Minneapolis, Minnesota 55455</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>Cancer Center, Center for Immunology, University of Minnesota, Minneapolis</wicri:cityArea></affiliation></author><author><name sortKey="Mansky, Louis M" sort="Mansky, Louis M" uniqKey="Mansky L" first="Louis M." last="Mansky">Louis M. Mansky</name><affiliation wicri:level="2"><nlm:aff id="aff4">Institute for Molecular Virology and Departments of Diagnostic and Biological Sciences and Microbiology, University of Minnesota Medical School, Minneapolis, Minnesota 55455</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>Institute for Molecular Virology and Departments of Diagnostic and Biological Sciences and Microbiology, University of Minnesota Medical School, Minneapolis</wicri:cityArea></affiliation></author><author><name sortKey="Geraghty, Robert J" sort="Geraghty, Robert J" uniqKey="Geraghty R" first="Robert J." last="Geraghty">Robert J. Geraghty</name><affiliation wicri:level="2"><nlm:aff id="aff2">Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>Center for Drug Design, University of Minnesota, Minneapolis</wicri:cityArea></affiliation></author><author><name sortKey="Li, Fang" sort="Li, Fang" uniqKey="Li F" first="Fang" last="Li">Fang Li</name><affiliation wicri:level="2"><nlm:aff id="aff1">Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>Department of Pharmacology, University of Minnesota Medical School, Minneapolis</wicri:cityArea></affiliation></author></analytic><series><title level="j">Journal of Virology</title><idno type="ISSN">0022-538X</idno><idno type="eISSN">1098-5514</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Coronavirus NL63, Human (physiology)</term><term>DNA Mutational Analysis</term><term>Humans</term><term>Peptidyl-Dipeptidase A (genetics)</term><term>Peptidyl-Dipeptidase A (metabolism)</term><term>Protein Binding</term><term>Receptors, Virus (genetics)</term><term>Receptors, Virus (metabolism)</term><term>SARS Virus (physiology)</term><term>Transduction, Genetic</term><term>Virus Attachment</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Analyse de mutations d'ADN</term><term>Attachement viral</term><term>Coronavirus humain NL63 (physiologie)</term><term>Humains</term><term>Liaison aux protéines</term><term>Peptidyl-Dipeptidase A (génétique)</term><term>Peptidyl-Dipeptidase A (métabolisme)</term><term>Récepteurs viraux (génétique)</term><term>Récepteurs viraux (métabolisme)</term><term>Transduction génétique</term><term>Virus du SRAS (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Peptidyl-Dipeptidase A</term><term>Receptors, Virus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Peptidyl-Dipeptidase A</term><term>Receptors, Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Peptidyl-Dipeptidase A</term><term>Récepteurs viraux</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Peptidyl-Dipeptidase A</term><term>Récepteurs viraux</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Coronavirus humain NL63</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Coronavirus NL63, Human</term><term>SARS Virus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>DNA Mutational Analysis</term><term>Humans</term><term>Protein Binding</term><term>Transduction, Genetic</term><term>Virus Attachment</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Analyse de mutations d'ADN</term><term>Attachement viral</term><term>Humains</term><term>Liaison aux protéines</term><term>Transduction génétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>How viruses evolve to select their receptor proteins for host cell entry is puzzling. We recently determined the crystal structures of NL63 coronavirus (NL63-CoV) and SARS coronavirus (SARS-CoV) receptor-binding domains (RBDs), each complexed with their common receptor, human angiotensin-converting enzyme 2 (hACE2), and proposed the existence of a virus-binding hot spot on hACE2. Here we investigated the function of this hypothetical hot spot using structure-guided biochemical and functional assays. The hot spot consists of a salt bridge surrounded by hydrophobic tunnel walls. Mutations that disturb the hot spot structure have significant effects on virus/receptor interactions, revealing critical energy contributions from the hot spot structure. The tunnel structure at the NL63-CoV/hACE2 interface is more compact than that at the SARS-CoV/hACE2 interface, and hence RBD/hACE2 binding affinities are decreased either by NL63-CoV mutations decreasing the tunnel space or by SARS-CoV mutations increasing the tunnel space. Furthermore, NL63-CoV RBD inhibits hACE2-dependent transduction by SARS-CoV spike protein, a successful application of the hot spot theory that has the potential to become a new antiviral strategy against SARS-CoV infections. These results suggest that the structural features of the hot spot on hACE2 were among the driving forces for the convergent evolution of NL63-CoV and SARS-CoV.</p></div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Minnesota</li></region></list><tree><country name="États-Unis"><region name="Minnesota"><name sortKey="Wu, Kailang" sort="Wu, Kailang" uniqKey="Wu K" first="Kailang" last="Wu">Kailang Wu</name></region><name sortKey="Chen, Lang" sort="Chen, Lang" uniqKey="Chen L" first="Lang" last="Chen">Lang Chen</name><name sortKey="Geraghty, Robert J" sort="Geraghty, Robert J" uniqKey="Geraghty R" first="Robert J." last="Geraghty">Robert J. Geraghty</name><name sortKey="Li, Fang" sort="Li, Fang" uniqKey="Li F" first="Fang" last="Li">Fang Li</name><name sortKey="Mansky, Louis M" sort="Mansky, Louis M" uniqKey="Mansky L" first="Louis M." last="Mansky">Louis M. Mansky</name><name sortKey="Peng, Guiqing" sort="Peng, Guiqing" uniqKey="Peng G" first="Guiqing" last="Peng">Guiqing Peng</name><name sortKey="Pennell, Christopher A" sort="Pennell, Christopher A" uniqKey="Pennell C" first="Christopher A." last="Pennell">Christopher A. Pennell</name><name sortKey="Zhou, Wenbo" sort="Zhou, Wenbo" uniqKey="Zhou W" first="Wenbo" last="Zhou">Wenbo Zhou</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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