Kinetic and Crystallographic Studies of Glucopyranosylidene Spirothiohydantoin Binding to Glycogen Phosphorylase b
Glucopyranosylidene spirothiohydantoin (TH) has been identified as a potential inhibitor of both muscle and liver glycogen phosphorylase b (GPb) and a (GPa) and shown to diminish liver GPa activity in vitro. Kinetic experiments reported here show that TH inhibits muscle GPb competitively with respec...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2002-02, Vol.10 (2), p.261-268 |
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| creator | Oikonomakos, Nikos G Skamnaki, Vicky T Ösz, Erzsébet Szilágyi, László Somsák, László Docsa, Tibor Tóth, Béla Gergely, Pál |
| description | Glucopyranosylidene spirothiohydantoin (TH) has been identified as a potential inhibitor of both muscle and liver glycogen phosphorylase b (GPb) and a (GPa) and shown to diminish liver GPa activity in vitro. Kinetic experiments reported here show that TH inhibits muscle GPb competitively with respect to both substrates phosphate (
K
i=2.3 μM) and glycogen (
K
i=2.8 μM). The structure of the GPb–TH complex has been determined at a resolution of 2.26 Å and refined to a crystallographic
R value of 0.193 (
R
free=0.211). The structure of GPb–TH complex reveals that the inhibitor can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provides a basis of understanding potency and specificity of the inhibitor. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the glucose complex, while the rigid thiohydantoin group is in a favourable electrostatic environment and makes additional polar contacts to the protein.
Electron density map of glucopyranosylidene thiohydantoin bound to glycogen phosphorylase b. |
| doi_str_mv | 10.1016/S0968-0896(01)00277-2 |
| format | Article |
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K
i=2.3 μM) and glycogen (
K
i=2.8 μM). The structure of the GPb–TH complex has been determined at a resolution of 2.26 Å and refined to a crystallographic
R value of 0.193 (
R
free=0.211). The structure of GPb–TH complex reveals that the inhibitor can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provides a basis of understanding potency and specificity of the inhibitor. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the glucose complex, while the rigid thiohydantoin group is in a favourable electrostatic environment and makes additional polar contacts to the protein.
Electron density map of glucopyranosylidene thiohydantoin bound to glycogen phosphorylase b.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/S0968-0896(01)00277-2</identifier><identifier>PMID: 11741774</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Animals ; Binding Sites ; Biological and medical sciences ; Catalytic Domain ; Crystallography, X-Ray ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - metabolism ; General and cellular metabolism. Vitamins ; Glycogen Phosphorylase, Muscle Form - antagonists & inhibitors ; Glycogen Phosphorylase, Muscle Form - chemistry ; Glycogen Phosphorylase, Muscle Form - metabolism ; Kinetics ; Medical sciences ; Models, Molecular ; Monosaccharides - chemistry ; Monosaccharides - metabolism ; Muscle, Skeletal - enzymology ; Pharmacology. Drug treatments ; Protein Conformation ; Rabbits ; Spiro Compounds - chemistry ; Spiro Compounds - metabolism</subject><ispartof>Bioorganic & medicinal chemistry, 2002-02, Vol.10 (2), p.261-268</ispartof><rights>2001 Elsevier Science Ltd</rights><rights>2002 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-91d62c40f2487a0c3ee49971bee68ba341e5708f6e342f02a3115985655b49d63</citedby><cites>FETCH-LOGICAL-c391t-91d62c40f2487a0c3ee49971bee68ba341e5708f6e342f02a3115985655b49d63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089601002772$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13395812$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11741774$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oikonomakos, Nikos G</creatorcontrib><creatorcontrib>Skamnaki, Vicky T</creatorcontrib><creatorcontrib>Ösz, Erzsébet</creatorcontrib><creatorcontrib>Szilágyi, László</creatorcontrib><creatorcontrib>Somsák, László</creatorcontrib><creatorcontrib>Docsa, Tibor</creatorcontrib><creatorcontrib>Tóth, Béla</creatorcontrib><creatorcontrib>Gergely, Pál</creatorcontrib><title>Kinetic and Crystallographic Studies of Glucopyranosylidene Spirothiohydantoin Binding to Glycogen Phosphorylase b</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>Glucopyranosylidene spirothiohydantoin (TH) has been identified as a potential inhibitor of both muscle and liver glycogen phosphorylase b (GPb) and a (GPa) and shown to diminish liver GPa activity in vitro. Kinetic experiments reported here show that TH inhibits muscle GPb competitively with respect to both substrates phosphate (
K
i=2.3 μM) and glycogen (
K
i=2.8 μM). The structure of the GPb–TH complex has been determined at a resolution of 2.26 Å and refined to a crystallographic
R value of 0.193 (
R
free=0.211). The structure of GPb–TH complex reveals that the inhibitor can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provides a basis of understanding potency and specificity of the inhibitor. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the glucose complex, while the rigid thiohydantoin group is in a favourable electrostatic environment and makes additional polar contacts to the protein.
Electron density map of glucopyranosylidene thiohydantoin bound to glycogen phosphorylase b.</description><subject>Animals</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Catalytic Domain</subject><subject>Crystallography, X-Ray</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Glycogen Phosphorylase, Muscle Form - antagonists & inhibitors</subject><subject>Glycogen Phosphorylase, Muscle Form - chemistry</subject><subject>Glycogen Phosphorylase, Muscle Form - metabolism</subject><subject>Kinetics</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Monosaccharides - chemistry</subject><subject>Monosaccharides - metabolism</subject><subject>Muscle, Skeletal - enzymology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Conformation</subject><subject>Rabbits</subject><subject>Spiro Compounds - chemistry</subject><subject>Spiro Compounds - metabolism</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkVGL1DAQx4Mo3nr6EZS-KOdDNdMmTfMkuugpHiisPoc0mW4j3aSXtEK__WVvF-_Rp4Hh958ZfkPIS6DvgELzfkdl05a0lc0VhbeUVkKU1SOyAdawsq4lPCabf8gFeZbSH5opJuEpuQAQDIRgGxK_O4-zM4X2ttjGNc16HMM-6mnIzd28WIepCH1xPS4mTGvUPqR1dBY9FrvJxTAPLgyr1X4OzhefnLfO74s55MRqwh598XMIaRpCXEedsOiekye9HhO-ONdL8vvL51_br-XNj-tv2483pcnXz6UE21SG0b5irdDU1IhMSgEdYtN2umaAXNC2b7BmVU8rXQNw2fKG845J29SX5M1p7hTD7YJpVgeXDI6j9hiWpATULZeCZ5CfQBNDShF7NUV30HFVQNVRtrqXrY4mFQV1L1tVOffqvGDpDmgfUme7GXh9BnQyeuyzPOPSA5ffxFs4Dvpw4jDr-OswqmQceoPWRTSzssH955Q7KwCdVQ</recordid><startdate>20020201</startdate><enddate>20020201</enddate><creator>Oikonomakos, Nikos G</creator><creator>Skamnaki, Vicky T</creator><creator>Ösz, Erzsébet</creator><creator>Szilágyi, László</creator><creator>Somsák, László</creator><creator>Docsa, Tibor</creator><creator>Tóth, Béla</creator><creator>Gergely, Pál</creator><general>Elsevier Ltd</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20020201</creationdate><title>Kinetic and Crystallographic Studies of Glucopyranosylidene Spirothiohydantoin Binding to Glycogen Phosphorylase b</title><author>Oikonomakos, Nikos G ; Skamnaki, Vicky T ; Ösz, Erzsébet ; Szilágyi, László ; Somsák, László ; Docsa, Tibor ; Tóth, Béla ; Gergely, Pál</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-91d62c40f2487a0c3ee49971bee68ba341e5708f6e342f02a3115985655b49d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Catalytic Domain</topic><topic>Crystallography, X-Ray</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Glycogen Phosphorylase, Muscle Form - antagonists & inhibitors</topic><topic>Glycogen Phosphorylase, Muscle Form - chemistry</topic><topic>Glycogen Phosphorylase, Muscle Form - metabolism</topic><topic>Kinetics</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Monosaccharides - chemistry</topic><topic>Monosaccharides - metabolism</topic><topic>Muscle, Skeletal - enzymology</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Conformation</topic><topic>Rabbits</topic><topic>Spiro Compounds - chemistry</topic><topic>Spiro Compounds - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Oikonomakos, Nikos G</creatorcontrib><creatorcontrib>Skamnaki, Vicky T</creatorcontrib><creatorcontrib>Ösz, Erzsébet</creatorcontrib><creatorcontrib>Szilágyi, László</creatorcontrib><creatorcontrib>Somsák, László</creatorcontrib><creatorcontrib>Docsa, Tibor</creatorcontrib><creatorcontrib>Tóth, Béla</creatorcontrib><creatorcontrib>Gergely, Pál</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oikonomakos, Nikos G</au><au>Skamnaki, Vicky T</au><au>Ösz, Erzsébet</au><au>Szilágyi, László</au><au>Somsák, László</au><au>Docsa, Tibor</au><au>Tóth, Béla</au><au>Gergely, Pál</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Kinetic and Crystallographic Studies of Glucopyranosylidene Spirothiohydantoin Binding to Glycogen Phosphorylase b</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2002-02-01</date><risdate>2002</risdate><volume>10</volume><issue>2</issue><spage>261</spage><epage>268</epage><pages>261-268</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>Glucopyranosylidene spirothiohydantoin (TH) has been identified as a potential inhibitor of both muscle and liver glycogen phosphorylase b (GPb) and a (GPa) and shown to diminish liver GPa activity in vitro. Kinetic experiments reported here show that TH inhibits muscle GPb competitively with respect to both substrates phosphate (
K
i=2.3 μM) and glycogen (
K
i=2.8 μM). The structure of the GPb–TH complex has been determined at a resolution of 2.26 Å and refined to a crystallographic
R value of 0.193 (
R
free=0.211). The structure of GPb–TH complex reveals that the inhibitor can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provides a basis of understanding potency and specificity of the inhibitor. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the glucose complex, while the rigid thiohydantoin group is in a favourable electrostatic environment and makes additional polar contacts to the protein.
Electron density map of glucopyranosylidene thiohydantoin bound to glycogen phosphorylase b.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>11741774</pmid><doi>10.1016/S0968-0896(01)00277-2</doi><tpages>8</tpages></addata></record> |
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| subjects | Animals Binding Sites Biological and medical sciences Catalytic Domain Crystallography, X-Ray Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism General and cellular metabolism. Vitamins Glycogen Phosphorylase, Muscle Form - antagonists & inhibitors Glycogen Phosphorylase, Muscle Form - chemistry Glycogen Phosphorylase, Muscle Form - metabolism Kinetics Medical sciences Models, Molecular Monosaccharides - chemistry Monosaccharides - metabolism Muscle, Skeletal - enzymology Pharmacology. Drug treatments Protein Conformation Rabbits Spiro Compounds - chemistry Spiro Compounds - metabolism |
| title | Kinetic and Crystallographic Studies of Glucopyranosylidene Spirothiohydantoin Binding to Glycogen Phosphorylase b |
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