Structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds.
Identifieur interne : 002A10 ( Main/Exploration ); précédent : 002A09; suivant : 002A11Structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds.
Auteurs : Cheng-Chung Lee [Taïwan] ; Chih-Jung Kuo ; Tzu-Ping Ko ; Min-Feng Hsu ; Yao-Chen Tsui ; Shih-Cheng Chang ; Syaulan Yang ; Shu-Jen Chen ; Hua-Chien Chen ; Ming-Chu Hsu ; Shin-Ru Shih ; Po-Huang Liang ; Andrew H-J WangSource :
- The Journal of biological chemistry [ 0021-9258 ] ; 2009.
Descripteurs français
- KwdFr :
- Cysteine endopeptidases (), Humains, Inhibiteurs de la cystéine protéinase (), Inhibiteurs de la cystéine protéinase (usage thérapeutique), Matériaux biomimétiques (), Matériaux biomimétiques (usage thérapeutique), Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Relation structure-activité, Sites de fixation, Structure tertiaire des protéines, Syndrome respiratoire aigu sévère (enzymologie), Syndrome respiratoire aigu sévère (traitement médicamenteux), Virus du SRAS (enzymologie), Zinc ().
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Syndrome respiratoire aigu sévère, Virus du SRAS.
- traitement médicamenteux : Syndrome respiratoire aigu sévère.
- usage thérapeutique : Inhibiteurs de la cystéine protéinase, Matériaux biomimétiques.
- Cysteine endopeptidases, Humains, Inhibiteurs de la cystéine protéinase, Matériaux biomimétiques, Protéines virales, Relation structure-activité, Sites de fixation, Structure tertiaire des protéines, Zinc.
English descriptors
- KwdEn :
- Binding Sites, Biomimetic Materials (chemistry), Biomimetic Materials (therapeutic use), Cysteine Endopeptidases (chemistry), Cysteine Proteinase Inhibitors (chemistry), Cysteine Proteinase Inhibitors (therapeutic use), Humans, Protein Structure, Tertiary, SARS Virus (enzymology), Severe Acute Respiratory Syndrome (drug therapy), Severe Acute Respiratory Syndrome (enzymology), Structure-Activity Relationship, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry), Zinc (chemistry).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemistry : Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Viral Proteins, Zinc.
- chemistry : Biomimetic Materials.
- drug therapy : Severe Acute Respiratory Syndrome.
- enzymology : SARS Virus, Severe Acute Respiratory Syndrome.
- therapeutic use : Biomimetic Materials, Cysteine Proteinase Inhibitors.
- Binding Sites, Humans, Protein Structure, Tertiary, Structure-Activity Relationship.
Abstract
Human coxsackievirus (CV) belongs to the picornavirus family, which consists of over 200 medically relevant viruses. In picornavirus, a chymotrypsin-like protease (3C(pro)) is required for viral replication by processing the polyproteins, and thus it is regarded as an antiviral drug target. A 3C-like protease (3CL(pro)) also exists in human coronaviruses (CoV) such as 229E and the one causing severe acute respiratory syndrome (SARS). To combat SARS, we previously had developed peptidomimetic and zinc-coordinating inhibitors of 3CL(pro). As shown in the present study, some of these compounds were also found to be active against 3C(pro) of CV strain B3 (CVB3). Several crystal structures of 3C(pro) from CVB3 and 3CL(pro) from CoV-229E and SARS-CoV in complex with the inhibitors were solved. The zinc-coordinating inhibitor is tetrahedrally coordinated to the His(40)-Cys(147) catalytic dyad of CVB3 3C(pro). The presence of specific binding pockets for the residues of peptidomimetic inhibitors explains the binding specificity. Our results provide a structural basis for inhibitor optimization and development of potential drugs for antiviral therapies.
DOI: 10.1074/jbc.M807947200
PubMed: 19144641
Affiliations:
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University, Taipei 11221, Taiwan.</nlm:affiliation><country xml:lang="fr">Taïwan</country><wicri:regionArea>Structural Biology Program, Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221</wicri:regionArea><wicri:noRegion>Taipei 11221</wicri:noRegion></affiliation></author><author><name sortKey="Kuo, Chih Jung" sort="Kuo, Chih Jung" uniqKey="Kuo C" first="Chih-Jung" last="Kuo">Chih-Jung Kuo</name></author><author><name sortKey="Ko, Tzu Ping" sort="Ko, Tzu Ping" uniqKey="Ko T" first="Tzu-Ping" last="Ko">Tzu-Ping Ko</name></author><author><name sortKey="Hsu, Min Feng" sort="Hsu, Min Feng" uniqKey="Hsu M" first="Min-Feng" last="Hsu">Min-Feng Hsu</name></author><author><name sortKey="Tsui, Yao Chen" sort="Tsui, Yao Chen" uniqKey="Tsui Y" first="Yao-Chen" last="Tsui">Yao-Chen Tsui</name></author><author><name sortKey="Chang, Shih Cheng" sort="Chang, Shih Cheng" uniqKey="Chang S" first="Shih-Cheng" last="Chang">Shih-Cheng Chang</name></author><author><name sortKey="Yang, Syaulan" sort="Yang, Syaulan" uniqKey="Yang S" first="Syaulan" last="Yang">Syaulan Yang</name></author><author><name sortKey="Chen, Shu Jen" sort="Chen, Shu Jen" uniqKey="Chen S" first="Shu-Jen" last="Chen">Shu-Jen Chen</name></author><author><name sortKey="Chen, Hua Chien" sort="Chen, Hua Chien" uniqKey="Chen H" first="Hua-Chien" last="Chen">Hua-Chien Chen</name></author><author><name sortKey="Hsu, Ming Chu" sort="Hsu, Ming Chu" uniqKey="Hsu M" first="Ming-Chu" last="Hsu">Ming-Chu Hsu</name></author><author><name sortKey="Shih, Shin Ru" sort="Shih, Shin Ru" uniqKey="Shih S" first="Shin-Ru" last="Shih">Shin-Ru Shih</name></author><author><name sortKey="Liang, Po Huang" sort="Liang, Po Huang" uniqKey="Liang P" first="Po-Huang" last="Liang">Po-Huang Liang</name></author><author><name sortKey="Wang, Andrew H J" sort="Wang, Andrew H J" uniqKey="Wang A" first="Andrew H-J" last="Wang">Andrew H-J Wang</name></author></analytic><series><title 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endopeptidases ()</term><term>Humains</term><term>Inhibiteurs de la cystéine protéinase ()</term><term>Inhibiteurs de la cystéine protéinase (usage thérapeutique)</term><term>Matériaux biomimétiques ()</term><term>Matériaux biomimétiques (usage thérapeutique)</term><term>Protéines virales ()</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Relation structure-activité</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Syndrome respiratoire aigu sévère (enzymologie)</term><term>Syndrome respiratoire aigu sévère (traitement médicamenteux)</term><term>Virus du SRAS (enzymologie)</term><term>Zinc ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Cysteine Proteinase Inhibitors</term><term>Viral 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thérapeutique" xml:lang="fr"><term>Inhibiteurs de la cystéine protéinase</term><term>Matériaux biomimétiques</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Humans</term><term>Protein Structure, Tertiary</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cysteine endopeptidases</term><term>Humains</term><term>Inhibiteurs de la cystéine protéinase</term><term>Matériaux biomimétiques</term><term>Protéines virales</term><term>Relation structure-activité</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Zinc</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Human coxsackievirus (CV) belongs to the picornavirus family, which consists of over 200 medically relevant viruses. In picornavirus, a chymotrypsin-like protease (3C(pro)) is required for viral replication by processing the polyproteins, and thus it is regarded as an antiviral drug target. A 3C-like protease (3CL(pro)) also exists in human coronaviruses (CoV) such as 229E and the one causing severe acute respiratory syndrome (SARS). To combat SARS, we previously had developed peptidomimetic and zinc-coordinating inhibitors of 3CL(pro). As shown in the present study, some of these compounds were also found to be active against 3C(pro) of CV strain B3 (CVB3). Several crystal structures of 3C(pro) from CVB3 and 3CL(pro) from CoV-229E and SARS-CoV in complex with the inhibitors were solved. The zinc-coordinating inhibitor is tetrahedrally coordinated to the His(40)-Cys(147) catalytic dyad of CVB3 3C(pro). The presence of specific binding pockets for the residues of peptidomimetic inhibitors explains the binding specificity. Our results provide a structural basis for inhibitor optimization and development of potential drugs for antiviral therapies.</div></front></TEI><affiliations><list><country><li>Taïwan</li></country></list><tree><noCountry><name sortKey="Chang, Shih Cheng" sort="Chang, Shih Cheng" uniqKey="Chang S" first="Shih-Cheng" last="Chang">Shih-Cheng Chang</name><name sortKey="Chen, Hua Chien" sort="Chen, Hua Chien" uniqKey="Chen H" first="Hua-Chien" last="Chen">Hua-Chien Chen</name><name sortKey="Chen, Shu Jen" sort="Chen, Shu Jen" uniqKey="Chen S" first="Shu-Jen" last="Chen">Shu-Jen Chen</name><name sortKey="Hsu, Min Feng" sort="Hsu, Min Feng" uniqKey="Hsu M" first="Min-Feng" last="Hsu">Min-Feng Hsu</name><name sortKey="Hsu, Ming Chu" sort="Hsu, Ming Chu" uniqKey="Hsu M" first="Ming-Chu" last="Hsu">Ming-Chu Hsu</name><name sortKey="Ko, Tzu Ping" sort="Ko, Tzu Ping" uniqKey="Ko T" first="Tzu-Ping" last="Ko">Tzu-Ping Ko</name><name sortKey="Kuo, Chih Jung" sort="Kuo, Chih Jung" uniqKey="Kuo C" first="Chih-Jung" last="Kuo">Chih-Jung Kuo</name><name sortKey="Liang, Po Huang" sort="Liang, Po Huang" uniqKey="Liang P" first="Po-Huang" last="Liang">Po-Huang Liang</name><name sortKey="Shih, Shin Ru" sort="Shih, Shin Ru" uniqKey="Shih S" first="Shin-Ru" last="Shih">Shin-Ru Shih</name><name sortKey="Tsui, Yao Chen" sort="Tsui, Yao Chen" uniqKey="Tsui Y" first="Yao-Chen" last="Tsui">Yao-Chen Tsui</name><name sortKey="Wang, Andrew H J" sort="Wang, Andrew H J" uniqKey="Wang A" first="Andrew H-J" last="Wang">Andrew H-J Wang</name><name sortKey="Yang, Syaulan" sort="Yang, Syaulan" uniqKey="Yang S" first="Syaulan" last="Yang">Syaulan Yang</name></noCountry><country name="Taïwan"><noRegion><name sortKey="Lee, Cheng Chung" sort="Lee, Cheng Chung" uniqKey="Lee C" first="Cheng-Chung" last="Lee">Cheng-Chung Lee</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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