An episulfide cation (thiiranium ring) trapped in the active site of HAV 3C proteinase inactivated by peptide-based ketone inhibitors.
Identifieur interne : 002157 ( PubMed/Corpus ); précédent : 002156; suivant : 002158An episulfide cation (thiiranium ring) trapped in the active site of HAV 3C proteinase inactivated by peptide-based ketone inhibitors.
Auteurs : Jiang Yin ; Maia M. Cherney ; Ernst M. Bergmann ; Jianmin Zhang ; Carly Huitema ; Hanna Pettersson ; Lindsay D. Eltis ; John C. Vederas ; Michael N G. JamesSource :
- Journal of molecular biology [ 0022-2836 ] ; 2006.
English descriptors
- KwdEn :
- Binding Sites, Crystallography, X-Ray, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Hepatitis A virus (chemistry), Hepatitis A virus (enzymology), Hydrolysis, Ketones (chemistry), Ketones (metabolism), Models, Molecular, Protease Inhibitors (chemistry), Protease Inhibitors (metabolism), Protein Conformation, Viral Proteins (chemistry), Viral Proteins (metabolism).
- MESH :
- chemical , chemistry : Cysteine Endopeptidases, Ketones, Protease Inhibitors, Viral Proteins.
- chemical , metabolism : Cysteine Endopeptidases, Ketones, Protease Inhibitors, Viral Proteins.
- chemistry : Hepatitis A virus.
- enzymology : Hepatitis A virus.
- Binding Sites, Crystallography, X-Ray, Hydrolysis, Models, Molecular, Protein Conformation.
Abstract
We have solved the crystal and molecular structures of hepatitis A viral (HAV) 3C proteinase, a cysteine peptidase having a chymotrypsin-like protein fold, in complex with each of three tetrapeptidyl-based methyl ketone inhibitors to resolutions beyond 1.4 A, the highest resolution to date for a 3C or a 3C-Like (e.g. SARS viral main proteinase) peptidase. The residues of the beta-hairpin motif (residues 138-158), an extension of two beta-strands of the C-terminal beta-barrel of HAV 3C are critical for the interactions between the enzyme and the tetrapeptide portion of these inhibitors that are analogous to the residues at the P4 to P1 positions in the natural substrates of picornaviral 3C proteinases. Unexpectedly, the Sgamma of Cys172 forms two covalent bonds with each inhibitor, yielding an unusual episulfide cation (thiiranium ring) stabilized by a nearby oxyanion. This result suggests a mechanism of inactivation of 3C peptidases by methyl ketone inhibitors that is distinct from that occurring in the structurally related serine proteinases or in the papain-like cysteine peptidases. It also provides insight into the mechanisms underlying both the inactivation of HAV 3C by these inhibitors and on the proteolysis of natural substrates by this viral cysteine peptidase.
DOI: 10.1016/j.jmb.2006.06.047
PubMed: 16860823
Links to Exploration step
pubmed:16860823Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">An episulfide cation (thiiranium ring) trapped in the active site of HAV 3C proteinase inactivated by peptide-based ketone inhibitors.</title><author><name sortKey="Yin, Jiang" sort="Yin, Jiang" uniqKey="Yin J" first="Jiang" last="Yin">Jiang Yin</name><affiliation><nlm:affiliation>Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, AB, Canada T6G 2H7.</nlm:affiliation></affiliation></author><author><name sortKey="Cherney, Maia M" sort="Cherney, Maia M" uniqKey="Cherney M" first="Maia M" last="Cherney">Maia M. Cherney</name></author><author><name sortKey="Bergmann, Ernst M" sort="Bergmann, Ernst M" uniqKey="Bergmann E" first="Ernst M" last="Bergmann">Ernst M. Bergmann</name></author><author><name sortKey="Zhang, Jianmin" sort="Zhang, Jianmin" uniqKey="Zhang J" first="Jianmin" last="Zhang">Jianmin Zhang</name></author><author><name sortKey="Huitema, Carly" sort="Huitema, Carly" uniqKey="Huitema C" first="Carly" last="Huitema">Carly Huitema</name></author><author><name sortKey="Pettersson, Hanna" sort="Pettersson, Hanna" uniqKey="Pettersson H" first="Hanna" last="Pettersson">Hanna Pettersson</name></author><author><name sortKey="Eltis, Lindsay D" sort="Eltis, Lindsay D" uniqKey="Eltis L" first="Lindsay D" last="Eltis">Lindsay D. Eltis</name></author><author><name sortKey="Vederas, John C" sort="Vederas, John C" uniqKey="Vederas J" first="John C" last="Vederas">John C. Vederas</name></author><author><name sortKey="James, Michael N G" sort="James, Michael N G" uniqKey="James M" first="Michael N G" last="James">Michael N G. James</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2006">2006</date><idno type="RBID">pubmed:16860823</idno><idno type="pmid">16860823</idno><idno type="doi">10.1016/j.jmb.2006.06.047</idno><idno type="wicri:Area/PubMed/Corpus">002157</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002157</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">An episulfide cation (thiiranium ring) trapped in the active site of HAV 3C proteinase inactivated by peptide-based ketone inhibitors.</title><author><name sortKey="Yin, Jiang" sort="Yin, Jiang" uniqKey="Yin J" first="Jiang" last="Yin">Jiang Yin</name><affiliation><nlm:affiliation>Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, AB, Canada T6G 2H7.</nlm:affiliation></affiliation></author><author><name sortKey="Cherney, Maia M" sort="Cherney, Maia M" uniqKey="Cherney M" first="Maia M" last="Cherney">Maia M. Cherney</name></author><author><name sortKey="Bergmann, Ernst M" sort="Bergmann, Ernst M" uniqKey="Bergmann E" first="Ernst M" last="Bergmann">Ernst M. Bergmann</name></author><author><name sortKey="Zhang, Jianmin" sort="Zhang, Jianmin" uniqKey="Zhang J" first="Jianmin" last="Zhang">Jianmin Zhang</name></author><author><name sortKey="Huitema, Carly" sort="Huitema, Carly" uniqKey="Huitema C" first="Carly" last="Huitema">Carly Huitema</name></author><author><name sortKey="Pettersson, Hanna" sort="Pettersson, Hanna" uniqKey="Pettersson H" first="Hanna" last="Pettersson">Hanna Pettersson</name></author><author><name sortKey="Eltis, Lindsay D" sort="Eltis, Lindsay D" uniqKey="Eltis L" first="Lindsay D" last="Eltis">Lindsay D. Eltis</name></author><author><name sortKey="Vederas, John C" sort="Vederas, John C" uniqKey="Vederas J" first="John C" last="Vederas">John C. Vederas</name></author><author><name sortKey="James, Michael N G" sort="James, Michael N G" uniqKey="James M" first="Michael N G" last="James">Michael N G. James</name></author></analytic><series><title level="j">Journal of molecular biology</title><idno type="ISSN">0022-2836</idno><imprint><date when="2006" type="published">2006</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Binding Sites</term><term>Crystallography, X-Ray</term><term>Cysteine Endopeptidases (chemistry)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Hepatitis A virus (chemistry)</term><term>Hepatitis A virus (enzymology)</term><term>Hydrolysis</term><term>Ketones (chemistry)</term><term>Ketones (metabolism)</term><term>Models, Molecular</term><term>Protease Inhibitors (chemistry)</term><term>Protease Inhibitors (metabolism)</term><term>Protein Conformation</term><term>Viral Proteins (chemistry)</term><term>Viral Proteins (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Ketones</term><term>Protease Inhibitors</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Ketones</term><term>Protease Inhibitors</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Hepatitis A virus</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Hepatitis A virus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Crystallography, X-Ray</term><term>Hydrolysis</term><term>Models, Molecular</term><term>Protein Conformation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We have solved the crystal and molecular structures of hepatitis A viral (HAV) 3C proteinase, a cysteine peptidase having a chymotrypsin-like protein fold, in complex with each of three tetrapeptidyl-based methyl ketone inhibitors to resolutions beyond 1.4 A, the highest resolution to date for a 3C or a 3C-Like (e.g. SARS viral main proteinase) peptidase. The residues of the beta-hairpin motif (residues 138-158), an extension of two beta-strands of the C-terminal beta-barrel of HAV 3C are critical for the interactions between the enzyme and the tetrapeptide portion of these inhibitors that are analogous to the residues at the P4 to P1 positions in the natural substrates of picornaviral 3C proteinases. Unexpectedly, the Sgamma of Cys172 forms two covalent bonds with each inhibitor, yielding an unusual episulfide cation (thiiranium ring) stabilized by a nearby oxyanion. This result suggests a mechanism of inactivation of 3C peptidases by methyl ketone inhibitors that is distinct from that occurring in the structurally related serine proteinases or in the papain-like cysteine peptidases. It also provides insight into the mechanisms underlying both the inactivation of HAV 3C by these inhibitors and on the proteolysis of natural substrates by this viral cysteine peptidase.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16860823</PMID><DateCompleted><Year>2006</Year><Month>10</Month><Day>04</Day></DateCompleted><DateRevised><Year>2007</Year><Month>10</Month><Day>11</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">0022-2836</ISSN><JournalIssue CitedMedium="Print"><Volume>361</Volume><Issue>4</Issue><PubDate><Year>2006</Year><Month>Aug</Month><Day>25</Day></PubDate></JournalIssue><Title>Journal of molecular biology</Title><ISOAbbreviation>J. Mol. Biol.</ISOAbbreviation></Journal><ArticleTitle>An episulfide cation (thiiranium ring) trapped in the active site of HAV 3C proteinase inactivated by peptide-based ketone inhibitors.</ArticleTitle><Pagination><MedlinePgn>673-86</MedlinePgn></Pagination><Abstract><AbstractText>We have solved the crystal and molecular structures of hepatitis A viral (HAV) 3C proteinase, a cysteine peptidase having a chymotrypsin-like protein fold, in complex with each of three tetrapeptidyl-based methyl ketone inhibitors to resolutions beyond 1.4 A, the highest resolution to date for a 3C or a 3C-Like (e.g. SARS viral main proteinase) peptidase. The residues of the beta-hairpin motif (residues 138-158), an extension of two beta-strands of the C-terminal beta-barrel of HAV 3C are critical for the interactions between the enzyme and the tetrapeptide portion of these inhibitors that are analogous to the residues at the P4 to P1 positions in the natural substrates of picornaviral 3C proteinases. Unexpectedly, the Sgamma of Cys172 forms two covalent bonds with each inhibitor, yielding an unusual episulfide cation (thiiranium ring) stabilized by a nearby oxyanion. This result suggests a mechanism of inactivation of 3C peptidases by methyl ketone inhibitors that is distinct from that occurring in the structurally related serine proteinases or in the papain-like cysteine peptidases. It also provides insight into the mechanisms underlying both the inactivation of HAV 3C by these inhibitors and on the proteolysis of natural substrates by this viral cysteine peptidase.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yin</LastName><ForeName>Jiang</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, AB, Canada T6G 2H7.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cherney</LastName><ForeName>Maia M</ForeName><Initials>MM</Initials></Author><Author ValidYN="Y"><LastName>Bergmann</LastName><ForeName>Ernst M</ForeName><Initials>EM</Initials></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Jianmin</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Huitema</LastName><ForeName>Carly</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Pettersson</LastName><ForeName>Hanna</ForeName><Initials>H</Initials></Author><Author ValidYN="Y"><LastName>Eltis</LastName><ForeName>Lindsay D</ForeName><Initials>LD</Initials></Author><Author ValidYN="Y"><LastName>Vederas</LastName><ForeName>John C</ForeName><Initials>JC</Initials></Author><Author ValidYN="Y"><LastName>James</LastName><ForeName>Michael N G</ForeName><Initials>MN</Initials></Author></AuthorList><Language>eng</Language><DataBankList CompleteYN="Y"><DataBank><DataBankName>PDB</DataBankName><AccessionNumberList><AccessionNumber>2H6M</AccessionNumber><AccessionNumber>2H94</AccessionNumber><AccessionNumber>2HAL</AccessionNumber></AccessionNumberList></DataBank></DataBankList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType 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