Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CLpro): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS.
Identifieur interne : 001289 ( Main/Exploration ); précédent : 001288; suivant : 001290Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CLpro): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS.
Auteurs : Sakshi Tomar ; Melanie L. Johnston [États-Unis] ; Sarah E. St John ; Heather L. Osswald [États-Unis] ; Prasanth R. Nyalapatla [États-Unis] ; Lake N. Paul ; Arun K. Ghosh [États-Unis] ; Mark R. Denison [États-Unis] ; Andrew D. Mesecar [États-Unis]Source :
- The Journal of biological chemistry [ 1083-351X ] ; 2015.
Descripteurs français
- KwdFr :
- Alignement de séquences, Antiviraux (), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Cinétique, Coronavirus du syndrome respiratoire du Moyen-Orient (), Coronavirus du syndrome respiratoire du Moyen-Orient (enzymologie), Coronavirus du syndrome respiratoire du Moyen-Orient (génétique), Cristallographie aux rayons X, Cysteine endopeptidases (), Cysteine endopeptidases (génétique), Cysteine endopeptidases (métabolisme), Données de séquences moléculaires, Escherichia coli (génétique), Escherichia coli (métabolisme), Expression des gènes, Interactions hydrophobes et hydrophiles, Ligands, Multimérisation de protéines (), Peptidomimétiques (), Peptidomimétiques (pharmacologie), Peptidomimétiques (synthèse chimique), Protéines recombinantes (), Protéines recombinantes (génétique), Protéines recombinantes (métabolisme), Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Protéines virales (génétique), Protéines virales (métabolisme), Simulation de docking moléculaire, Spécificité du substrat, Séquence d'acides aminés.
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Coronavirus du syndrome respiratoire du Moyen-Orient.
- génétique : Coronavirus du syndrome respiratoire du Moyen-Orient, Cysteine endopeptidases, Escherichia coli, Protéines recombinantes, Protéines virales.
- métabolisme : Cysteine endopeptidases, Escherichia coli, Protéines recombinantes, Protéines virales.
- pharmacologie : Antiviraux, Peptidomimétiques.
- synthèse chimique : Antiviraux, Peptidomimétiques.
- Alignement de séquences, Antiviraux, Cinétique, Coronavirus du syndrome respiratoire du Moyen-Orient, Cristallographie aux rayons X, Cysteine endopeptidases, Données de séquences moléculaires, Expression des gènes, Interactions hydrophobes et hydrophiles, Ligands, Multimérisation de protéines, Peptidomimétiques, Protéines recombinantes, Protéines virales, Simulation de docking moléculaire, Spécificité du substrat, Séquence d'acides aminés.
English descriptors
- KwdEn :
- Amino Acid Sequence, Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Crystallography, X-Ray, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (genetics), Cysteine Endopeptidases (metabolism), Escherichia coli (genetics), Escherichia coli (metabolism), Gene Expression, Hydrophobic and Hydrophilic Interactions, Kinetics, Ligands, Middle East Respiratory Syndrome Coronavirus (drug effects), Middle East Respiratory Syndrome Coronavirus (enzymology), Middle East Respiratory Syndrome Coronavirus (genetics), Molecular Docking Simulation, Molecular Sequence Data, Peptidomimetics (chemical synthesis), Peptidomimetics (chemistry), Peptidomimetics (pharmacology), Protein Multimerization (drug effects), Recombinant Proteins (chemistry), Recombinant Proteins (genetics), Recombinant Proteins (metabolism), Sequence Alignment, Substrate Specificity, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry), Viral Proteins (genetics), Viral Proteins (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Antiviral Agents, Peptidomimetics.
- chemical , chemistry : Antiviral Agents, Cysteine Endopeptidases, Peptidomimetics, Recombinant Proteins, Viral Proteins.
- chemical , genetics : Cysteine Endopeptidases, Recombinant Proteins, Viral Proteins.
- chemical , metabolism : Cysteine Endopeptidases, Recombinant Proteins, Viral Proteins.
- chemical , pharmacology : Antiviral Agents, Peptidomimetics.
- drug effects : Middle East Respiratory Syndrome Coronavirus, Protein Multimerization.
- enzymology : Middle East Respiratory Syndrome Coronavirus.
- genetics : Escherichia coli, Middle East Respiratory Syndrome Coronavirus.
- metabolism : Escherichia coli.
- Amino Acid Sequence, Crystallography, X-Ray, Gene Expression, Hydrophobic and Hydrophilic Interactions, Kinetics, Ligands, Molecular Docking Simulation, Molecular Sequence Data, Sequence Alignment, Substrate Specificity.
Abstract
All coronaviruses, including the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) from the β-CoV subgroup, require the proteolytic activity of the nsp5 protease (also known as 3C-like protease, 3CL(pro)) during virus replication, making it a high value target for the development of anti-coronavirus therapeutics. Kinetic studies indicate that in contrast to 3CL(pro) from other β-CoV 2c members, including HKU4 and HKU5, MERS-CoV 3CL(pro) is less efficient at processing a peptide substrate due to MERS-CoV 3CL(pro) being a weakly associated dimer. Conversely, HKU4, HKU5, and SARS-CoV 3CL(pro) enzymes are tightly associated dimers. Analytical ultracentrifugation studies support that MERS-CoV 3CL(pro) is a weakly associated dimer (Kd ∼52 μm) with a slow off-rate. Peptidomimetic inhibitors of MERS-CoV 3CL(pro) were synthesized and utilized in analytical ultracentrifugation experiments and demonstrate that MERS-CoV 3CL(pro) undergoes significant ligand-induced dimerization. Kinetic studies also revealed that designed reversible inhibitors act as activators at a low compound concentration as a result of induced dimerization. Primary sequence comparisons and x-ray structural analyses of two MERS-CoV 3CLpro and inhibitor complexes, determined to 1.6 Å, reveal remarkable structural similarity of the dimer interface with 3CL(pro) from HKU4-CoV and HKU5-CoV. Despite this structural similarity, substantial differences in the dimerization ability suggest that long range interactions by the nonconserved amino acids distant from the dimer interface may control MERS-CoV 3CL(pro) dimerization. Activation of MERS-CoV 3CL(pro) through ligand-induced dimerization appears to be unique within the genogroup 2c and may potentially increase the complexity in the development of MERS-CoV 3CL(pro) inhibitors as antiviral agents.
DOI: 10.1074/jbc.M115.651463
PubMed: 26055715
Affiliations:
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Johnston</name><affiliation wicri:level="2"><nlm:affiliation>Chemistry, Purdue University, West Lafayette, Indiana 47907.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Chemistry, Purdue University, West Lafayette</wicri:cityArea></affiliation></author><author><name sortKey="St John, Sarah E" sort="St John, Sarah E" uniqKey="St John S" first="Sarah E" last="St John">Sarah E. St John</name><affiliation><nlm:affiliation>From the Departments of Biological Sciences and.</nlm:affiliation><wicri:noCountry code="no comma">From the Departments of Biological Sciences and.</wicri:noCountry></affiliation></author><author><name sortKey="Osswald, Heather L" sort="Osswald, Heather L" uniqKey="Osswald H" first="Heather L" last="Osswald">Heather L. 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Denison</name><affiliation wicri:level="2"><nlm:affiliation>the Departments of Pediatrics and Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>the Departments of Pediatrics and Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D" last="Mesecar">Andrew D. Mesecar</name><affiliation wicri:level="1"><nlm:affiliation>From the Departments of Biological Sciences and Chemistry, Purdue University, West Lafayette, Indiana 47907, amesecar@purdue.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>From the Departments of Biological Sciences and Chemistry, Purdue University, West Lafayette, Indiana 47907</wicri:regionArea><wicri:noRegion>Indiana 47907</wicri:noRegion></affiliation></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Antiviral Agents (chemical synthesis)</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Crystallography, X-Ray</term><term>Cysteine Endopeptidases (chemistry)</term><term>Cysteine Endopeptidases (genetics)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Escherichia coli (genetics)</term><term>Escherichia coli (metabolism)</term><term>Gene Expression</term><term>Hydrophobic and Hydrophilic Interactions</term><term>Kinetics</term><term>Ligands</term><term>Middle East Respiratory Syndrome Coronavirus (drug effects)</term><term>Middle East Respiratory Syndrome Coronavirus (enzymology)</term><term>Middle East Respiratory Syndrome Coronavirus (genetics)</term><term>Molecular Docking Simulation</term><term>Molecular Sequence Data</term><term>Peptidomimetics (chemical synthesis)</term><term>Peptidomimetics (chemistry)</term><term>Peptidomimetics (pharmacology)</term><term>Protein Multimerization (drug effects)</term><term>Recombinant Proteins (chemistry)</term><term>Recombinant Proteins (genetics)</term><term>Recombinant Proteins (metabolism)</term><term>Sequence Alignment</term><term>Substrate Specificity</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (chemistry)</term><term>Viral Proteins (genetics)</term><term>Viral Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Alignement de séquences</term><term>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Antiviraux (synthèse chimique)</term><term>Cinétique</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (enzymologie)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (génétique)</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases ()</term><term>Cysteine endopeptidases (génétique)</term><term>Cysteine endopeptidases (métabolisme)</term><term>Données de séquences moléculaires</term><term>Escherichia coli (génétique)</term><term>Escherichia coli (métabolisme)</term><term>Expression des gènes</term><term>Interactions hydrophobes et hydrophiles</term><term>Ligands</term><term>Multimérisation de protéines ()</term><term>Peptidomimétiques ()</term><term>Peptidomimétiques (pharmacologie)</term><term>Peptidomimétiques (synthèse chimique)</term><term>Protéines recombinantes ()</term><term>Protéines recombinantes (génétique)</term><term>Protéines recombinantes (métabolisme)</term><term>Protéines virales ()</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Protéines virales (génétique)</term><term>Protéines virales (métabolisme)</term><term>Simulation de docking moléculaire</term><term>Spécificité du substrat</term><term>Séquence d'acides aminés</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiviral Agents</term><term>Peptidomimetics</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Cysteine Endopeptidases</term><term>Peptidomimetics</term><term>Recombinant Proteins</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Recombinant Proteins</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Recombinant Proteins</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Peptidomimetics</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term><term>Protein Multimerization</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Escherichia coli</term><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Cysteine endopeptidases</term><term>Escherichia coli</term><term>Protéines recombinantes</term><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Escherichia coli</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cysteine endopeptidases</term><term>Escherichia coli</term><term>Protéines recombinantes</term><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Peptidomimétiques</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antiviraux</term><term>Peptidomimétiques</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Crystallography, X-Ray</term><term>Gene Expression</term><term>Hydrophobic and Hydrophilic Interactions</term><term>Kinetics</term><term>Ligands</term><term>Molecular Docking Simulation</term><term>Molecular Sequence Data</term><term>Sequence Alignment</term><term>Substrate Specificity</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Alignement de séquences</term><term>Antiviraux</term><term>Cinétique</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases</term><term>Données de séquences moléculaires</term><term>Expression des gènes</term><term>Interactions hydrophobes et hydrophiles</term><term>Ligands</term><term>Multimérisation de protéines</term><term>Peptidomimétiques</term><term>Protéines recombinantes</term><term>Protéines virales</term><term>Simulation de docking moléculaire</term><term>Spécificité du substrat</term><term>Séquence d'acides aminés</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">All coronaviruses, including the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) from the β-CoV subgroup, require the proteolytic activity of the nsp5 protease (also known as 3C-like protease, 3CL(pro)) during virus replication, making it a high value target for the development of anti-coronavirus therapeutics. Kinetic studies indicate that in contrast to 3CL(pro) from other β-CoV 2c members, including HKU4 and HKU5, MERS-CoV 3CL(pro) is less efficient at processing a peptide substrate due to MERS-CoV 3CL(pro) being a weakly associated dimer. Conversely, HKU4, HKU5, and SARS-CoV 3CL(pro) enzymes are tightly associated dimers. Analytical ultracentrifugation studies support that MERS-CoV 3CL(pro) is a weakly associated dimer (Kd ∼52 μm) with a slow off-rate. Peptidomimetic inhibitors of MERS-CoV 3CL(pro) were synthesized and utilized in analytical ultracentrifugation experiments and demonstrate that MERS-CoV 3CL(pro) undergoes significant ligand-induced dimerization. Kinetic studies also revealed that designed reversible inhibitors act as activators at a low compound concentration as a result of induced dimerization. Primary sequence comparisons and x-ray structural analyses of two MERS-CoV 3CLpro and inhibitor complexes, determined to 1.6 Å, reveal remarkable structural similarity of the dimer interface with 3CL(pro) from HKU4-CoV and HKU5-CoV. Despite this structural similarity, substantial differences in the dimerization ability suggest that long range interactions by the nonconserved amino acids distant from the dimer interface may control MERS-CoV 3CL(pro) dimerization. Activation of MERS-CoV 3CL(pro) through ligand-induced dimerization appears to be unique within the genogroup 2c and may potentially increase the complexity in the development of MERS-CoV 3CL(pro) inhibitors as antiviral agents. </div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Indiana</li><li>Tennessee</li></region></list><tree><noCountry><name sortKey="Paul, Lake N" sort="Paul, Lake N" uniqKey="Paul L" first="Lake N" last="Paul">Lake N. Paul</name><name sortKey="St John, Sarah E" sort="St John, Sarah E" uniqKey="St John S" first="Sarah E" last="St John">Sarah E. St John</name><name sortKey="Tomar, Sakshi" sort="Tomar, Sakshi" uniqKey="Tomar S" first="Sakshi" last="Tomar">Sakshi Tomar</name></noCountry><country name="États-Unis"><region name="Indiana"><name sortKey="Johnston, Melanie L" sort="Johnston, Melanie L" uniqKey="Johnston M" first="Melanie L" last="Johnston">Melanie L. Johnston</name></region><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R" last="Denison">Mark R. Denison</name><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K" last="Ghosh">Arun K. Ghosh</name><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D" last="Mesecar">Andrew D. Mesecar</name><name sortKey="Nyalapatla, Prasanth R" sort="Nyalapatla, Prasanth R" uniqKey="Nyalapatla P" first="Prasanth R" last="Nyalapatla">Prasanth R. Nyalapatla</name><name sortKey="Osswald, Heather L" sort="Osswald, Heather L" uniqKey="Osswald H" first="Heather L" last="Osswald">Heather L. Osswald</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001289 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 001289 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= SrasV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:26055715
|texte= Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CLpro): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:26055715" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a SrasV1
| This area was generated with Dilib version V0.6.33. |  |