Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding
Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-c...
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| Veröffentlicht in: | Molecular pharmacology 2015-12, Vol.88 (6), p.982-992 |
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| creator | Stein, Adam J Bain, Gretchen Prodanovich, Pat Santini, Angelina M Darlington, Janice Stelzer, Nina M P Sidhu, Ranjinder S Schaub, Jeffrey Goulet, Lance Lonergan, Dave Calderon, Imelda Evans, Jilly F Hutchinson, John H |
| description | Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors. |
| doi_str_mv | 10.1124/mol.115.100404 |
| format | Article |
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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors.</description><identifier>ISSN: 0026-895X</identifier><identifier>ISSN: 1521-0111</identifier><identifier>EISSN: 1521-0111</identifier><identifier>DOI: 10.1124/mol.115.100404</identifier><identifier>PMID: 26371182</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Cell Line, Tumor ; Crystallization ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - metabolism ; HEK293 Cells ; Humans ; Mice ; Phosphoric Diester Hydrolases - chemistry ; Phosphoric Diester Hydrolases - metabolism ; Protein Binding - physiology ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Structure-Activity Relationship</subject><ispartof>Molecular pharmacology, 2015-12, Vol.88 (6), p.982-992</ispartof><rights>Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-f716252a367af7d82890b86951c76db8621f22e84fd0df9d076a39dd8e76f9553</citedby><cites>FETCH-LOGICAL-c362t-f716252a367af7d82890b86951c76db8621f22e84fd0df9d076a39dd8e76f9553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,887,27933,27934</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26371182$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1498378$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Stein, Adam J</creatorcontrib><creatorcontrib>Bain, Gretchen</creatorcontrib><creatorcontrib>Prodanovich, Pat</creatorcontrib><creatorcontrib>Santini, Angelina M</creatorcontrib><creatorcontrib>Darlington, Janice</creatorcontrib><creatorcontrib>Stelzer, Nina M P</creatorcontrib><creatorcontrib>Sidhu, Ranjinder S</creatorcontrib><creatorcontrib>Schaub, Jeffrey</creatorcontrib><creatorcontrib>Goulet, Lance</creatorcontrib><creatorcontrib>Lonergan, Dave</creatorcontrib><creatorcontrib>Calderon, Imelda</creatorcontrib><creatorcontrib>Evans, Jilly F</creatorcontrib><creatorcontrib>Hutchinson, John H</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors.</description><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>Crystallization</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Mice</subject><subject>Phosphoric Diester Hydrolases - chemistry</subject><subject>Phosphoric Diester Hydrolases - metabolism</subject><subject>Protein Binding - physiology</subject><subject>Protein Structure, Secondary</subject><subject>Protein Structure, Tertiary</subject><subject>Structure-Activity Relationship</subject><issn>0026-895X</issn><issn>1521-0111</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kUlvFDEUhC1ERIbAlSOyOHHpwc_dXvqYTMgiBSUSIHGzPF4YR9324EUh_56OJuH06vBVqfQKoQ9A1gB0-DKnaRFsDYQMZHiFVsAodAQAXqMVIZR3cmS_jtHbUu4JgYFJ8gYdU94LAElX6P57zc3UlvWEz3QJBfuU8XXchW2oIUWcPL5qs474tNVU9d8Q8fYRX6SW8V2qLla8SfM-tWgLfgh1h89DqSGair8l68qT_yxEG-Lvd-jI66m498_3BP28-Ppjc9Xd3F5eb05vOtNzWjsvgFNGdc-F9sJKKkeylXxkYAS3i6LgKXVy8JZYP1oiuO5Ha6UT3I-M9Sfo0yE3LUVUMaE6szMpRmeqgmGUvZAL9PkA7XP601ypag7FuGnS0aVWFAgqueCDGBZ0fUBNTqVk59U-h1nnRwVEPY2glhEWwdRhhMXw8Tm7bWdn_-MvX-__AcIvgjY</recordid><startdate>20151201</startdate><enddate>20151201</enddate><creator>Stein, Adam J</creator><creator>Bain, Gretchen</creator><creator>Prodanovich, Pat</creator><creator>Santini, Angelina M</creator><creator>Darlington, Janice</creator><creator>Stelzer, Nina M P</creator><creator>Sidhu, Ranjinder S</creator><creator>Schaub, Jeffrey</creator><creator>Goulet, Lance</creator><creator>Lonergan, Dave</creator><creator>Calderon, Imelda</creator><creator>Evans, Jilly F</creator><creator>Hutchinson, John H</creator><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><scope>OTOTI</scope></search><sort><creationdate>20151201</creationdate><title>Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding</title><author>Stein, Adam J ; Bain, Gretchen ; Prodanovich, Pat ; Santini, Angelina M ; Darlington, Janice ; Stelzer, Nina M P ; Sidhu, Ranjinder S ; Schaub, Jeffrey ; Goulet, Lance ; Lonergan, Dave ; Calderon, Imelda ; Evans, Jilly F ; Hutchinson, John H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-f716252a367af7d82890b86951c76db8621f22e84fd0df9d076a39dd8e76f9553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>Crystallization</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Mice</topic><topic>Phosphoric Diester Hydrolases - chemistry</topic><topic>Phosphoric Diester Hydrolases - metabolism</topic><topic>Protein Binding - physiology</topic><topic>Protein Structure, Secondary</topic><topic>Protein Structure, Tertiary</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stein, Adam J</creatorcontrib><creatorcontrib>Bain, Gretchen</creatorcontrib><creatorcontrib>Prodanovich, Pat</creatorcontrib><creatorcontrib>Santini, Angelina M</creatorcontrib><creatorcontrib>Darlington, Janice</creatorcontrib><creatorcontrib>Stelzer, Nina M P</creatorcontrib><creatorcontrib>Sidhu, Ranjinder S</creatorcontrib><creatorcontrib>Schaub, Jeffrey</creatorcontrib><creatorcontrib>Goulet, Lance</creatorcontrib><creatorcontrib>Lonergan, Dave</creatorcontrib><creatorcontrib>Calderon, Imelda</creatorcontrib><creatorcontrib>Evans, Jilly F</creatorcontrib><creatorcontrib>Hutchinson, John H</creatorcontrib><creatorcontrib>Argonne National Lab. 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| subjects | Animals Cell Line, Tumor Crystallization Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism HEK293 Cells Humans Mice Phosphoric Diester Hydrolases - chemistry Phosphoric Diester Hydrolases - metabolism Protein Binding - physiology Protein Structure, Secondary Protein Structure, Tertiary Structure-Activity Relationship |
| title | Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding |
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