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Serial Crystallography for Structure-Based Drug Discovery
Rational drug discovery has greatly accelerated the development of safer and more efficacious therapeutics, assisted significantly by insights from experimentally determined 3D structures of ligands in complex with their targets. Serial crystallography (SX) with X-ray free-electron lasers has enable...
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Published in: | Trends in pharmacological sciences (Regular ed.) 2020-11, Vol.41 (11), p.830-839 |
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description | Rational drug discovery has greatly accelerated the development of safer and more efficacious therapeutics, assisted significantly by insights from experimentally determined 3D structures of ligands in complex with their targets. Serial crystallography (SX) with X-ray free-electron lasers has enabled structural determination using micrometer- or nanometer-size crystals. This technology, applied in the past decade to solve structures of notoriously difficult-to-study drug targets at room temperature, has now been adapted for use in synchrotron radiation facilities. Ultrashort time scales allow time-resolved characterization of dynamic structural changes and pave the road to study the molecular mechanisms by ‘molecular movie.’ This article summarizes the latest progress in SX technology and deliberates its demanding applications in future structure-based drug discovery.
X-ray free-electron lasers (XFELs) outrun radiation damage to enable room temperature structure determination of challenging proteins with microcrystals, overcoming the limitations of conventional crystallography to power up structure-based drug discovery (SBDD).The latest developments in sample delivery system and data analysis strategies have facilitated serial crystallography (SX).Ultrafast XFEL pulses allow time-resolved studies at subpicosecond scale, providing new structural insights into conformational dynamics of ligands with pharmaceutical targets.The evolution of experimental operation from XFELs to synchrotron beamlines boosts the applicability and accessibility of SX.Complex lipidic cubic phase technology has been applied in SX to determine multiple structures of ligand–protein complexes, shortening the timelines for structure determination and accelerating its application in SBDD. |
doi_str_mv | 10.1016/j.tips.2020.08.009 |
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X-ray free-electron lasers (XFELs) outrun radiation damage to enable room temperature structure determination of challenging proteins with microcrystals, overcoming the limitations of conventional crystallography to power up structure-based drug discovery (SBDD).The latest developments in sample delivery system and data analysis strategies have facilitated serial crystallography (SX).Ultrafast XFEL pulses allow time-resolved studies at subpicosecond scale, providing new structural insights into conformational dynamics of ligands with pharmaceutical targets.The evolution of experimental operation from XFELs to synchrotron beamlines boosts the applicability and accessibility of SX.Complex lipidic cubic phase technology has been applied in SX to determine multiple structures of ligand–protein complexes, shortening the timelines for structure determination and accelerating its application in SBDD.</description><identifier>ISSN: 0165-6147</identifier><identifier>EISSN: 1873-3735</identifier><identifier>DOI: 10.1016/j.tips.2020.08.009</identifier><identifier>PMID: 32950259</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Crystallography, X-Ray - instrumentation ; Crystallography, X-Ray - methods ; Drug Discovery - instrumentation ; Drug Discovery - methods ; GPCR ligand swapping ; Humans ; Lasers ; Protein Conformation ; Receptors, G-Protein-Coupled - chemistry ; Receptors, G-Protein-Coupled - metabolism ; serial femtosecond crystallography ; Structure-Activity Relationship ; structure-based drug discovery (SBDD) ; synchrotron-based serial crystallography ; Synchrotrons ; time-resolved serial crystallography ; X-ray free-electron laser (XFEL)</subject><ispartof>Trends in pharmacological sciences (Regular ed.), 2020-11, Vol.41 (11), p.830-839</ispartof><rights>2020 Elsevier Ltd</rights><rights>Copyright © 2020 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-9f0219218a125cd82b2c3e09c54d8e913c8ae80dc02ff88f81a2518c02386b843</citedby><cites>FETCH-LOGICAL-c455t-9f0219218a125cd82b2c3e09c54d8e913c8ae80dc02ff88f81a2518c02386b843</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32950259$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhu, Lan</creatorcontrib><creatorcontrib>Chen, Xiaoyu</creatorcontrib><creatorcontrib>Abola, Enrique E.</creatorcontrib><creatorcontrib>Jing, Liang</creatorcontrib><creatorcontrib>Liu, Wei</creatorcontrib><title>Serial Crystallography for Structure-Based Drug Discovery</title><title>Trends in pharmacological sciences (Regular ed.)</title><addtitle>Trends Pharmacol Sci</addtitle><description>Rational drug discovery has greatly accelerated the development of safer and more efficacious therapeutics, assisted significantly by insights from experimentally determined 3D structures of ligands in complex with their targets. Serial crystallography (SX) with X-ray free-electron lasers has enabled structural determination using micrometer- or nanometer-size crystals. This technology, applied in the past decade to solve structures of notoriously difficult-to-study drug targets at room temperature, has now been adapted for use in synchrotron radiation facilities. Ultrashort time scales allow time-resolved characterization of dynamic structural changes and pave the road to study the molecular mechanisms by ‘molecular movie.’ This article summarizes the latest progress in SX technology and deliberates its demanding applications in future structure-based drug discovery.
X-ray free-electron lasers (XFELs) outrun radiation damage to enable room temperature structure determination of challenging proteins with microcrystals, overcoming the limitations of conventional crystallography to power up structure-based drug discovery (SBDD).The latest developments in sample delivery system and data analysis strategies have facilitated serial crystallography (SX).Ultrafast XFEL pulses allow time-resolved studies at subpicosecond scale, providing new structural insights into conformational dynamics of ligands with pharmaceutical targets.The evolution of experimental operation from XFELs to synchrotron beamlines boosts the applicability and accessibility of SX.Complex lipidic cubic phase technology has been applied in SX to determine multiple structures of ligand–protein complexes, shortening the timelines for structure determination and accelerating its application in SBDD.</description><subject>Crystallography, X-Ray - instrumentation</subject><subject>Crystallography, X-Ray - methods</subject><subject>Drug Discovery - instrumentation</subject><subject>Drug Discovery - methods</subject><subject>GPCR ligand swapping</subject><subject>Humans</subject><subject>Lasers</subject><subject>Protein Conformation</subject><subject>Receptors, G-Protein-Coupled - chemistry</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>serial femtosecond crystallography</subject><subject>Structure-Activity Relationship</subject><subject>structure-based drug discovery (SBDD)</subject><subject>synchrotron-based serial crystallography</subject><subject>Synchrotrons</subject><subject>time-resolved serial crystallography</subject><subject>X-ray free-electron laser (XFEL)</subject><issn>0165-6147</issn><issn>1873-3735</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kE1LKzEUhoMoWj_-gIvLLN3MeJJMZhIQQesnCC7UdUgzZ2rKtKnJTKH_3pR6RTeuDuE875vkIeSUQkGBVuezonfLWDBgUIAsANQOGVFZ85zXXOySUYJEXtGyPiCHMc4AgHNG98kBZ0oAE2pE1AsGZ7psHNaxN13np8Es39dZ60P20ofB9kPA_NpEbLKbMEyzGxetX2FYH5O91nQRT77mEXm7u30dP-RPz_eP46un3JZC9LlqgVHFqDSUCdtINmGWIygrykaiotxKgxIaC6xtpWwlNUxQmY5cVhNZ8iNyue1dDpM5NhYXfTCdXgY3N2GtvXH692bh3vXUr3QtaiZBpIKzr4LgPwaMvZ6nP2DXmQX6IWpWlmUFUlV1QtkWtcHHGLD9voaC3jjXM71xrjfONUidnKfQv58P_I78l5yAiy2ASdPKYdDROlxYbFxA2-vGu7_6PwGRHpNh</recordid><startdate>20201101</startdate><enddate>20201101</enddate><creator>Zhu, Lan</creator><creator>Chen, Xiaoyu</creator><creator>Abola, Enrique E.</creator><creator>Jing, Liang</creator><creator>Liu, Wei</creator><general>Elsevier Ltd</general><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>5PM</scope></search><sort><creationdate>20201101</creationdate><title>Serial Crystallography for Structure-Based Drug Discovery</title><author>Zhu, Lan ; Chen, Xiaoyu ; Abola, Enrique E. ; Jing, Liang ; Liu, Wei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-9f0219218a125cd82b2c3e09c54d8e913c8ae80dc02ff88f81a2518c02386b843</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Crystallography, X-Ray - instrumentation</topic><topic>Crystallography, X-Ray - methods</topic><topic>Drug Discovery - instrumentation</topic><topic>Drug Discovery - methods</topic><topic>GPCR ligand swapping</topic><topic>Humans</topic><topic>Lasers</topic><topic>Protein Conformation</topic><topic>Receptors, G-Protein-Coupled - chemistry</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>serial femtosecond crystallography</topic><topic>Structure-Activity Relationship</topic><topic>structure-based drug discovery (SBDD)</topic><topic>synchrotron-based serial crystallography</topic><topic>Synchrotrons</topic><topic>time-resolved serial crystallography</topic><topic>X-ray free-electron laser (XFEL)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhu, Lan</creatorcontrib><creatorcontrib>Chen, Xiaoyu</creatorcontrib><creatorcontrib>Abola, Enrique E.</creatorcontrib><creatorcontrib>Jing, Liang</creatorcontrib><creatorcontrib>Liu, Wei</creatorcontrib><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Trends in pharmacological sciences (Regular ed.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhu, Lan</au><au>Chen, Xiaoyu</au><au>Abola, Enrique E.</au><au>Jing, Liang</au><au>Liu, Wei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Serial Crystallography for Structure-Based Drug Discovery</atitle><jtitle>Trends in pharmacological sciences (Regular ed.)</jtitle><addtitle>Trends Pharmacol Sci</addtitle><date>2020-11-01</date><risdate>2020</risdate><volume>41</volume><issue>11</issue><spage>830</spage><epage>839</epage><pages>830-839</pages><issn>0165-6147</issn><eissn>1873-3735</eissn><abstract>Rational drug discovery has greatly accelerated the development of safer and more efficacious therapeutics, assisted significantly by insights from experimentally determined 3D structures of ligands in complex with their targets. Serial crystallography (SX) with X-ray free-electron lasers has enabled structural determination using micrometer- or nanometer-size crystals. This technology, applied in the past decade to solve structures of notoriously difficult-to-study drug targets at room temperature, has now been adapted for use in synchrotron radiation facilities. Ultrashort time scales allow time-resolved characterization of dynamic structural changes and pave the road to study the molecular mechanisms by ‘molecular movie.’ This article summarizes the latest progress in SX technology and deliberates its demanding applications in future structure-based drug discovery.
X-ray free-electron lasers (XFELs) outrun radiation damage to enable room temperature structure determination of challenging proteins with microcrystals, overcoming the limitations of conventional crystallography to power up structure-based drug discovery (SBDD).The latest developments in sample delivery system and data analysis strategies have facilitated serial crystallography (SX).Ultrafast XFEL pulses allow time-resolved studies at subpicosecond scale, providing new structural insights into conformational dynamics of ligands with pharmaceutical targets.The evolution of experimental operation from XFELs to synchrotron beamlines boosts the applicability and accessibility of SX.Complex lipidic cubic phase technology has been applied in SX to determine multiple structures of ligand–protein complexes, shortening the timelines for structure determination and accelerating its application in SBDD.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>32950259</pmid><doi>10.1016/j.tips.2020.08.009</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Crystallography, X-Ray - instrumentation Crystallography, X-Ray - methods Drug Discovery - instrumentation Drug Discovery - methods GPCR ligand swapping Humans Lasers Protein Conformation Receptors, G-Protein-Coupled - chemistry Receptors, G-Protein-Coupled - metabolism serial femtosecond crystallography Structure-Activity Relationship structure-based drug discovery (SBDD) synchrotron-based serial crystallography Synchrotrons time-resolved serial crystallography X-ray free-electron laser (XFEL) |
title | Serial Crystallography for Structure-Based Drug Discovery |
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