Three-dimensional domain swapping as a mechanism to lock the active conformation in a super-active octamer of SARS-CoV main protease.
Identifieur interne : 002415 ( Main/Exploration ); précédent : 002414; suivant : 002416Three-dimensional domain swapping as a mechanism to lock the active conformation in a super-active octamer of SARS-CoV main protease.
Auteurs : Shengnan Zhang [République populaire de Chine] ; Nan Zhong [République populaire de Chine] ; Fei Xue [République populaire de Chine] ; Xue Kang [République populaire de Chine] ; Xiaobai Ren [République populaire de Chine] ; Jiaxuan Chen [République populaire de Chine] ; Changwen Jin [République populaire de Chine] ; Zhiyong Lou [République populaire de Chine] ; Bin Xia [République populaire de Chine]Source :
- Protein & cell [ 1674-8018 ] ; 2010.
Descripteurs français
- KwdFr :
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , chemistry : Peptides, Polyproteins.
- chemical , metabolism : Endopeptidases, Peptides, Polyproteins.
- chemical : Cysteine Endopeptidases, Viral Proteins.
- chemistry : SARS Virus.
- metabolism : Coronavirus, SARS Virus.
- Humans, Protein Binding.
Abstract
Proteolytic processing of viral polyproteins is indispensible for the lifecycle of coronaviruses. The main protease (M(pro)) of SARS-CoV is an attractive target for anti-SARS drug development as it is essential for the polyprotein processing. M(pro) is initially produced as part of viral polyproteins and it is matured by autocleavage. Here, we report that, with the addition of an N-terminal extension peptide, M(pro) can form a domain-swapped dimer. After complete removal of the extension peptide from the dimer, the mature M(pro) self-assembles into a novel super-active octamer (AO-M(pro)). The crystal structure of AO-M(pro) adopts a novel fold with four domain-swapped dimers packing into four active units with nearly identical conformation to that of the previously reported M(pro) active dimer, and 3D domain swapping serves as a mechanism to lock the active conformation due to entanglement of polypeptide chains. Compared with the previously well characterized form of M(pro), in equilibrium between inactive monomer and active dimer, the stable AO-M(pro) exhibits much higher proteolytic activity at low concentration. As all eight active sites are bound with inhibitors, the polyvalent nature of the interaction between AO-M(pro) and its polyprotein substrates with multiple cleavage sites, would make AO-M(pro) functionally much more superior than the M(pro) active dimer for polyprotein processing. Thus, during the initial period of SARS-CoV infection, this novel active form AOM(pro) should play a major role in cleaving polyproteins as the protein level is extremely low. The discovery of AOM(pro) provides new insights about the functional mechanism of M(pro) and its maturation process.
DOI: 10.1007/s13238-010-0044-8
PubMed: 21203949
Affiliations:
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last="Zhang">Shengnan Zhang</name><affiliation wicri:level="4"><nlm:affiliation>Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing, 100871, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing, 100871</wicri:regionArea><orgName type="university">Université de Pékin</orgName><placeName><settlement type="city">Pékin</settlement><region type="capitale">Pékin</region></placeName></affiliation></author><author><name sortKey="Zhong, Nan" sort="Zhong, Nan" uniqKey="Zhong N" first="Nan" last="Zhong">Nan Zhong</name><affiliation wicri:level="4"><nlm:affiliation>Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing, 100871, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing, 100871</wicri:regionArea><orgName 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de Chine</country><wicri:regionArea>Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing, 100871</wicri:regionArea><orgName type="university">Université de Pékin</orgName><placeName><settlement type="city">Pékin</settlement><region type="capitale">Pékin</region></placeName></affiliation></author></analytic><series><title level="j">Protein & cell</title><idno type="eISSN">1674-8018</idno><imprint><date when="2010" type="published">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Coronavirus (metabolism)</term><term>Cysteine Endopeptidases</term><term>Endopeptidases (metabolism)</term><term>Humans</term><term>Peptides (chemistry)</term><term>Peptides (metabolism)</term><term>Polyproteins (chemistry)</term><term>Polyproteins (metabolism)</term><term>Protein Binding</term><term>SARS Virus (chemistry)</term><term>SARS Virus (metabolism)</term><term>Viral Proteins</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Coronavirus (métabolisme)</term><term>Cysteine endopeptidases</term><term>Endopeptidases (métabolisme)</term><term>Humains</term><term>Liaison aux protéines</term><term>Peptides ()</term><term>Peptides (métabolisme)</term><term>Polyprotéines ()</term><term>Polyprotéines (métabolisme)</term><term>Protéines virales</term><term>Virus du SRAS ()</term><term>Virus du SRAS (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Peptides</term><term>Polyproteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Endopeptidases</term><term>Peptides</term><term>Polyproteins</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Coronavirus</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Coronavirus</term><term>Endopeptidases</term><term>Peptides</term><term>Polyprotéines</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Humans</term><term>Protein Binding</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cysteine endopeptidases</term><term>Humains</term><term>Liaison aux protéines</term><term>Peptides</term><term>Polyprotéines</term><term>Protéines virales</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Proteolytic processing of viral polyproteins is indispensible for the lifecycle of coronaviruses. The main protease (M(pro)) of SARS-CoV is an attractive target for anti-SARS drug development as it is essential for the polyprotein processing. M(pro) is initially produced as part of viral polyproteins and it is matured by autocleavage. Here, we report that, with the addition of an N-terminal extension peptide, M(pro) can form a domain-swapped dimer. After complete removal of the extension peptide from the dimer, the mature M(pro) self-assembles into a novel super-active octamer (AO-M(pro)). The crystal structure of AO-M(pro) adopts a novel fold with four domain-swapped dimers packing into four active units with nearly identical conformation to that of the previously reported M(pro) active dimer, and 3D domain swapping serves as a mechanism to lock the active conformation due to entanglement of polypeptide chains. Compared with the previously well characterized form of M(pro), in equilibrium between inactive monomer and active dimer, the stable AO-M(pro) exhibits much higher proteolytic activity at low concentration. As all eight active sites are bound with inhibitors, the polyvalent nature of the interaction between AO-M(pro) and its polyprotein substrates with multiple cleavage sites, would make AO-M(pro) functionally much more superior than the M(pro) active dimer for polyprotein processing. Thus, during the initial period of SARS-CoV infection, this novel active form AOM(pro) should play a major role in cleaving polyproteins as the protein level is extremely low. The discovery of AOM(pro) provides new insights about the functional mechanism of M(pro) and its maturation process.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country><region><li>Pékin</li></region><settlement><li>Pékin</li></settlement><orgName><li>Université de Pékin</li></orgName></list><tree><country name="République populaire de Chine"><region name="Pékin"><name sortKey="Zhang, Shengnan" sort="Zhang, Shengnan" uniqKey="Zhang S" first="Shengnan" last="Zhang">Shengnan Zhang</name></region><name sortKey="Chen, Jiaxuan" sort="Chen, Jiaxuan" uniqKey="Chen J" first="Jiaxuan" last="Chen">Jiaxuan Chen</name><name sortKey="Jin, Changwen" sort="Jin, Changwen" uniqKey="Jin C" first="Changwen" last="Jin">Changwen Jin</name><name sortKey="Kang, Xue" sort="Kang, Xue" uniqKey="Kang X" first="Xue" last="Kang">Xue Kang</name><name sortKey="Lou, Zhiyong" sort="Lou, Zhiyong" uniqKey="Lou Z" first="Zhiyong" last="Lou">Zhiyong Lou</name><name sortKey="Ren, Xiaobai" sort="Ren, Xiaobai" uniqKey="Ren X" first="Xiaobai" last="Ren">Xiaobai Ren</name><name sortKey="Xia, Bin" sort="Xia, Bin" uniqKey="Xia B" first="Bin" last="Xia">Bin Xia</name><name sortKey="Xue, Fei" sort="Xue, Fei" uniqKey="Xue F" first="Fei" last="Xue">Fei Xue</name><name sortKey="Zhong, Nan" sort="Zhong, Nan" uniqKey="Zhong N" first="Nan" last="Zhong">Nan Zhong</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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