How does the exosite of rhomboid protease affect substrate processing and inhibition?
Rhomboid proteases constitute a family of intramembrane serine proteases ubiquitous in all forms of life. They differ in many aspects from their soluble counterparts. We applied molecular dynamics (MD) computational approach to address several challenging issues regarding their catalytic mechanism:...
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| Veröffentlicht in: | Protein science 2017-12, Vol.26 (12), p.2355-2366 |
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| creator | Shokhen, Michael Albeck, Amnon |
| description | Rhomboid proteases constitute a family of intramembrane serine proteases ubiquitous in all forms of life. They differ in many aspects from their soluble counterparts. We applied molecular dynamics (MD) computational approach to address several challenging issues regarding their catalytic mechanism: How does the exosite of GlpG rhomboid protease control the kinetics efficiency of substrate hydrolysis? What is the mechanism of inhibition by the non‐competitive peptidyl aldehyde inhibitors bound to the GlpG rhomboid active site (AS)? What is the underlying mechanism that explains the hypothesis that GlpG rhomboid protease is not adopted for the hydrolysis of short peptides that do not contain a transmembrane domain (TMD)? Two fundamental features of rhomboid catalysis, the enzyme recognition and discrimination of substrates by TMD interactions in the exosite, and the concerted mechanism of non‐covalent pre‐catalytic complex to covalent tetrahedral complex (TC) conversion, provide answers to these mechanistic questions. |
| doi_str_mv | 10.1002/pro.3294 |
| format | Article |
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They differ in many aspects from their soluble counterparts. We applied molecular dynamics (MD) computational approach to address several challenging issues regarding their catalytic mechanism: How does the exosite of GlpG rhomboid protease control the kinetics efficiency of substrate hydrolysis? What is the mechanism of inhibition by the non‐competitive peptidyl aldehyde inhibitors bound to the GlpG rhomboid active site (AS)? What is the underlying mechanism that explains the hypothesis that GlpG rhomboid protease is not adopted for the hydrolysis of short peptides that do not contain a transmembrane domain (TMD)? Two fundamental features of rhomboid catalysis, the enzyme recognition and discrimination of substrates by TMD interactions in the exosite, and the concerted mechanism of non‐covalent pre‐catalytic complex to covalent tetrahedral complex (TC) conversion, provide answers to these mechanistic questions.</description><subject>Catalysis</subject><subject>Catalytic converters</subject><subject>Computer applications</subject><subject>Coordination compounds</subject><subject>effector</subject><subject>exosite</subject><subject>Feature recognition</subject><subject>Hydrolysis</subject><subject>Kinetics</subject><subject>membrane enzymes</subject><subject>Molecular dynamics</subject><subject>Peptides</subject><subject>Protease</subject><subject>Proteinase</subject><subject>Reaction kinetics</subject><subject>rhomboid</subject><subject>Serine</subject><subject>serine proteases</subject><subject>Substrate inhibition</subject><subject>Substrates</subject><issn>0961-8368</issn><issn>1469-896X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNp1kclKBDEQhoMoOi7gE0jAi5fWbJ1OLoqIGwiKKHgL6Z6KE-npjEm3y9sb9wU8FUV9fPzFj9A6JduUELYzi2GbMy3m0IgKqQul5c08GhEtaaG4VEtoOaU7QoigjC-iJaaUEkpUI3R9Eh7xOEDC_QQwPIXke8DB4TgJ0zr4Mc7uHmwCbJ2DpsdpqFMfbabypYGUfHeLbTfGvpv42vc-dHuraMHZNsHax1xB10eHVwcnxdn58enB_lnRlESIwknlhMhhaK0qpqgWvNFalY6XkgkLRFPdOFKLiqiaE0G4dKJiJadUWqctX0G7797ZUE9h3ECXk7VmFv3UxmcTrDe_L52fmNvwYEqptVAqC7Y-BDHcD5B6M_Wpgba1HYQhGap5VTLGBMvo5h_0Lgyxy-9lSkpdak7Yt7CJIaUI7isMJea1q7wH89pVRjd-hv8CP8vJQPEOPPoWnv8VmYvL8zfhC9tWnVk</recordid><startdate>201712</startdate><enddate>201712</enddate><creator>Shokhen, Michael</creator><creator>Albeck, Amnon</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7T5</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6531-9109</orcidid></search><sort><creationdate>201712</creationdate><title>How does the exosite of rhomboid protease affect substrate processing and inhibition?</title><author>Shokhen, Michael ; Albeck, Amnon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5044-f68f442881b87281943c9985f35624ae0919cf0b4708b304036f47253116af9a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Catalysis</topic><topic>Catalytic converters</topic><topic>Computer applications</topic><topic>Coordination compounds</topic><topic>effector</topic><topic>exosite</topic><topic>Feature recognition</topic><topic>Hydrolysis</topic><topic>Kinetics</topic><topic>membrane enzymes</topic><topic>Molecular dynamics</topic><topic>Peptides</topic><topic>Protease</topic><topic>Proteinase</topic><topic>Reaction kinetics</topic><topic>rhomboid</topic><topic>Serine</topic><topic>serine proteases</topic><topic>Substrate inhibition</topic><topic>Substrates</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shokhen, Michael</creatorcontrib><creatorcontrib>Albeck, Amnon</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Protein science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shokhen, Michael</au><au>Albeck, Amnon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>How does the exosite of rhomboid protease affect substrate processing and inhibition?</atitle><jtitle>Protein science</jtitle><addtitle>Protein Sci</addtitle><date>2017-12</date><risdate>2017</risdate><volume>26</volume><issue>12</issue><spage>2355</spage><epage>2366</epage><pages>2355-2366</pages><issn>0961-8368</issn><eissn>1469-896X</eissn><abstract>Rhomboid proteases constitute a family of intramembrane serine proteases ubiquitous in all forms of life. They differ in many aspects from their soluble counterparts. We applied molecular dynamics (MD) computational approach to address several challenging issues regarding their catalytic mechanism: How does the exosite of GlpG rhomboid protease control the kinetics efficiency of substrate hydrolysis? What is the mechanism of inhibition by the non‐competitive peptidyl aldehyde inhibitors bound to the GlpG rhomboid active site (AS)? What is the underlying mechanism that explains the hypothesis that GlpG rhomboid protease is not adopted for the hydrolysis of short peptides that do not contain a transmembrane domain (TMD)? 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| source | Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley Free Content; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Catalysis Catalytic converters Computer applications Coordination compounds effector exosite Feature recognition Hydrolysis Kinetics membrane enzymes Molecular dynamics Peptides Protease Proteinase Reaction kinetics rhomboid Serine serine proteases Substrate inhibition Substrates |
| title | How does the exosite of rhomboid protease affect substrate processing and inhibition? |
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