NMR and MD Studies Reveal That the Isolated Dengue NS3 Protease Is an Intrinsically Disordered Chymotrypsin Fold Which Absolutely Requests NS2B for Correct Folding and Functional Dynamics.
Identifieur interne : 000D84 ( PubMed/Checkpoint ); précédent : 000D83; suivant : 000D85NMR and MD Studies Reveal That the Isolated Dengue NS3 Protease Is an Intrinsically Disordered Chymotrypsin Fold Which Absolutely Requests NS2B for Correct Folding and Functional Dynamics.
Auteurs : Garvita Gupta [Singapour] ; Liangzhong Lim [Singapour] ; Jianxing Song [Singapour]Source :
- PloS one [ 1932-6203 ] ; 2015.
Descripteurs français
- KwdFr :
- Chymotrypsine (), Dengue (virologie), Dichroïsme circulaire, Endopeptidases (), Escherichia coli (métabolisme), Génome viral, Liaison aux protéines, Marqueurs de spin, Micelles, Mutagenèse dirigée, Pliage des protéines, Protéines virales non structurales (), RNA helicases (), Relation structure-activité, Serine endopeptidases (), Simulation de dynamique moléculaire, Spectroscopie par résonance magnétique, Structure secondaire des protéines, Virus de la dengue ().
- MESH :
- métabolisme : Escherichia coli.
- virologie : Dengue.
- Chymotrypsine, Dichroïsme circulaire, Endopeptidases, Génome viral, Liaison aux protéines, Marqueurs de spin, Micelles, Mutagenèse dirigée, Pliage des protéines, Protéines virales non structurales, RNA helicases, Relation structure-activité, Serine endopeptidases, Simulation de dynamique moléculaire, Spectroscopie par résonance magnétique, Structure secondaire des protéines, Virus de la dengue.
English descriptors
- KwdEn :
- Chymotrypsin (chemistry), Circular Dichroism, Dengue (virology), Dengue Virus (chemistry), Endopeptidases (chemistry), Escherichia coli (metabolism), Genome, Viral, Magnetic Resonance Spectroscopy, Micelles, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Protein Binding, Protein Folding, Protein Structure, Secondary, RNA Helicases (chemistry), Serine Endopeptidases (chemistry), Spin Labels, Structure-Activity Relationship, Viral Nonstructural Proteins (chemistry).
- MESH :
- chemical , chemistry : Chymotrypsin, Endopeptidases, RNA Helicases, Serine Endopeptidases, Viral Nonstructural Proteins.
- chemistry : Dengue Virus.
- metabolism : Escherichia coli.
- virology : Dengue.
- Circular Dichroism, Genome, Viral, Magnetic Resonance Spectroscopy, Micelles, Molecular Dynamics Simulation, Mutagenesis, Site-Directed, Protein Binding, Protein Folding, Protein Structure, Secondary, Spin Labels, Structure-Activity Relationship.
Abstract
Dengue genome encodes a two component protease complex (NS2B-NS3pro) essential for the viral maturation/infectivity, thus representing a key drug target. Previously, due to its "complete insolubility", the isolated NS3pro could not be experimentally studied and it remains elusive what structure it adopts without NS2B and why NS2B is indispensable. Here as facilitated by our previous discovery, the isolated NS3pro has been surprisingly deciphered by NMR to be the first intrinsically-disordered chymotrypsin-like fold, which exists in a loosely-packed state with non-native long-range interactions as revealed by paramagnetic relaxation enhancement (PRE). The disordered NS3pro appears to be needed for binding a human host factor to trigger the membrane remodeling. Moreover, we have in vitro refolded the NS3pro in complex with either NS2B (48-100) or the full-length NS2B (1-130) anchored into the LMPC micelle, and the two complexes have similar activities but different dynamics. We also performed molecular dynamics (MD) simulations and the results revealed that NS2B shows the highest structural fluctuations in the complex, thus providing the dynamic basis for the observation on its conformational exchange between open and closed states. Remarkably, the NS2B cofactor plays a central role in maintaining the correlated motion network required for the catalysis as we previously decoded for the SARS 3CL protease. Indeed, a truncated NS2B (48-100;Δ77-84) with the flexible loop deleted is able to trap the NS2B-NS3pro complex in a highly dynamic and catalytically-impotent state. Taken together, our study implies potential strategies to perturb the NS2B-NS3pro interface for design of inhibitors for treating dengue infection.
DOI: 10.1371/journal.pone.0134823
PubMed: 26258523
Affiliations:
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Previously, due to its "complete insolubility", the isolated NS3pro could not be experimentally studied and it remains elusive what structure it adopts without NS2B and why NS2B is indispensable. Here as facilitated by our previous discovery, the isolated NS3pro has been surprisingly deciphered by NMR to be the first intrinsically-disordered chymotrypsin-like fold, which exists in a loosely-packed state with non-native long-range interactions as revealed by paramagnetic relaxation enhancement (PRE). The disordered NS3pro appears to be needed for binding a human host factor to trigger the membrane remodeling. Moreover, we have in vitro refolded the NS3pro in complex with either NS2B (48-100) or the full-length NS2B (1-130) anchored into the LMPC micelle, and the two complexes have similar activities but different dynamics. We also performed molecular dynamics (MD) simulations and the results revealed that NS2B shows the highest structural fluctuations in the complex, thus providing the dynamic basis for the observation on its conformational exchange between open and closed states. Remarkably, the NS2B cofactor plays a central role in maintaining the correlated motion network required for the catalysis as we previously decoded for the SARS 3CL protease. Indeed, a truncated NS2B (48-100;Δ77-84) with the flexible loop deleted is able to trap the NS2B-NS3pro complex in a highly dynamic and catalytically-impotent state. Taken together, our study implies potential strategies to perturb the NS2B-NS3pro interface for design of inhibitors for treating dengue infection. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26258523</PMID><DateCompleted><Year>2016</Year><Month>05</Month><Day>23</Day></DateCompleted><DateRevised><Year>2020</Year><Month>03</Month><Day>06</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1932-6203</ISSN><JournalIssue CitedMedium="Internet"><Volume>10</Volume><Issue>8</Issue><PubDate><Year>2015</Year></PubDate></JournalIssue><Title>PloS one</Title><ISOAbbreviation>PLoS ONE</ISOAbbreviation></Journal><ArticleTitle>NMR and MD Studies Reveal That the Isolated Dengue NS3 Protease Is an Intrinsically Disordered Chymotrypsin Fold Which Absolutely Requests NS2B for Correct Folding and Functional Dynamics.</ArticleTitle><Pagination><MedlinePgn>e0134823</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.pone.0134823</ELocationID><Abstract><AbstractText>Dengue genome encodes a two component protease complex (NS2B-NS3pro) essential for the viral maturation/infectivity, thus representing a key drug target. Previously, due to its "complete insolubility", the isolated NS3pro could not be experimentally studied and it remains elusive what structure it adopts without NS2B and why NS2B is indispensable. Here as facilitated by our previous discovery, the isolated NS3pro has been surprisingly deciphered by NMR to be the first intrinsically-disordered chymotrypsin-like fold, which exists in a loosely-packed state with non-native long-range interactions as revealed by paramagnetic relaxation enhancement (PRE). The disordered NS3pro appears to be needed for binding a human host factor to trigger the membrane remodeling. Moreover, we have in vitro refolded the NS3pro in complex with either NS2B (48-100) or the full-length NS2B (1-130) anchored into the LMPC micelle, and the two complexes have similar activities but different dynamics. We also performed molecular dynamics (MD) simulations and the results revealed that NS2B shows the highest structural fluctuations in the complex, thus providing the dynamic basis for the observation on its conformational exchange between open and closed states. Remarkably, the NS2B cofactor plays a central role in maintaining the correlated motion network required for the catalysis as we previously decoded for the SARS 3CL protease. Indeed, a truncated NS2B (48-100;Δ77-84) with the flexible loop deleted is able to trap the NS2B-NS3pro complex in a highly dynamic and catalytically-impotent state. Taken together, our study implies potential strategies to perturb the NS2B-NS3pro interface for design of inhibitors for treating dengue infection. </AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Gupta</LastName><ForeName>Garvita</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore, Singapore.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lim</LastName><ForeName>Liangzhong</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore, Singapore.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Song</LastName><ForeName>Jianxing</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore, Singapore.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>08</Month><Day>10</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>PLoS One</MedlineTA><NlmUniqueID>101285081</NlmUniqueID><ISSNLinking>1932-6203</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008823">Micelles</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C080102">NS2B protein, flavivirus</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C060028">NS3 protein, 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MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002942" MajorTopicYN="N">Circular Dichroism</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003715" MajorTopicYN="N">Dengue</DescriptorName><QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003716" MajorTopicYN="N">Dengue Virus</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010450" MajorTopicYN="N">Endopeptidases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004926" MajorTopicYN="N">Escherichia coli</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016679" MajorTopicYN="N">Genome, Viral</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009682" MajorTopicYN="N">Magnetic Resonance Spectroscopy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008823" MajorTopicYN="N">Micelles</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D056004" MajorTopicYN="N">Molecular Dynamics Simulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016297" MajorTopicYN="N">Mutagenesis, Site-Directed</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011485" MajorTopicYN="N">Protein Binding</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017510" MajorTopicYN="N">Protein Folding</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017433" MajorTopicYN="N">Protein Structure, Secondary</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020365" MajorTopicYN="N">RNA Helicases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012697" MajorTopicYN="N">Serine Endopeptidases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013113" MajorTopicYN="N">Spin Labels</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017361" MajorTopicYN="N">Viral Nonstructural Proteins</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>05</Month><Day>14</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>07</Month><Day>14</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>8</Month><Day>11</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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