Analysis of phosphoinositide 3-kinase inhibitors by bottom-up electron-transfer dissociation hydrogen/deuterium exchange mass spectrometry
Until recently, one of the major limitations of hydrogen/deuterium exchange mass spectrometry (HDX-MS) was the peptide-level resolution afforded by proteolytic digestion. This limitation can be selectively overcome through the use of electron-transfer dissociation to fragment peptides in a manner th...
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| Veröffentlicht in: | Biochemical journal 2017-06, Vol.474 (11), p.1867-1877 |
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| creator | Masson, Glenn R Maslen, Sarah L Williams, Roger L |
| description | Until recently, one of the major limitations of hydrogen/deuterium exchange mass spectrometry (HDX-MS) was the peptide-level resolution afforded by proteolytic digestion. This limitation can be selectively overcome through the use of electron-transfer dissociation to fragment peptides in a manner that allows the retention of the deuterium signal to produce hydrogen/deuterium exchange tandem mass spectrometry (HDX-MS/MS). Here, we describe the application of HDX-MS/MS to structurally screen inhibitors of the oncogene phosphoinositide 3-kinase catalytic p110α subunit. HDX-MS/MS analysis is able to discern a conserved mechanism of inhibition common to a range of inhibitors. Owing to the relatively minor amounts of protein required, this technique may be utilised in pharmaceutical development for screening potential therapeutics. |
| doi_str_mv | 10.1042/BCJ20170127 |
| format | Article |
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This limitation can be selectively overcome through the use of electron-transfer dissociation to fragment peptides in a manner that allows the retention of the deuterium signal to produce hydrogen/deuterium exchange tandem mass spectrometry (HDX-MS/MS). Here, we describe the application of HDX-MS/MS to structurally screen inhibitors of the oncogene phosphoinositide 3-kinase catalytic p110α subunit. HDX-MS/MS analysis is able to discern a conserved mechanism of inhibition common to a range of inhibitors. 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This limitation can be selectively overcome through the use of electron-transfer dissociation to fragment peptides in a manner that allows the retention of the deuterium signal to produce hydrogen/deuterium exchange tandem mass spectrometry (HDX-MS/MS). Here, we describe the application of HDX-MS/MS to structurally screen inhibitors of the oncogene phosphoinositide 3-kinase catalytic p110α subunit. HDX-MS/MS analysis is able to discern a conserved mechanism of inhibition common to a range of inhibitors. Owing to the relatively minor amounts of protein required, this technique may be utilised in pharmaceutical development for screening potential therapeutics.</description><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - metabolism</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Binding Sites</subject><subject>Class I Phosphatidylinositol 3-Kinases</subject><subject>Class Ia Phosphatidylinositol 3-Kinase - chemistry</subject><subject>Class Ia Phosphatidylinositol 3-Kinase - genetics</subject><subject>Class Ia Phosphatidylinositol 3-Kinase - metabolism</subject><subject>Deuterium Exchange Measurement</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Electron Transport</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Indazoles - chemistry</subject><subject>Indazoles - metabolism</subject><subject>Indazoles - pharmacology</subject><subject>Models, Molecular</subject><subject>Molecular Weight</subject><subject>Oligonucleotides - antagonists & inhibitors</subject><subject>Oligonucleotides - chemistry</subject><subject>Oligonucleotides - genetics</subject><subject>Oligonucleotides - metabolism</subject><subject>Peptide Fragments - antagonists & inhibitors</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - genetics</subject><subject>Peptide Fragments - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - chemistry</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoinositide-3 Kinase Inhibitors</subject><subject>Protein Conformation</subject><subject>Purines - chemistry</subject><subject>Purines - metabolism</subject><subject>Purines - pharmacology</subject><subject>Pyridazines</subject><subject>Quinazolinones - chemistry</subject><subject>Quinazolinones - metabolism</subject><subject>Quinazolinones - pharmacology</subject><subject>Quinolines - chemistry</subject><subject>Quinolines - metabolism</subject><subject>Quinolines - pharmacology</subject><subject>Recombinant Fusion Proteins - chemistry</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Reproducibility of Results</subject><subject>Signal Processing, Computer-Assisted</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - metabolism</subject><subject>Sulfonamides - pharmacology</subject><subject>Tandem Mass Spectrometry</subject><subject>Triazines - chemistry</subject><subject>Triazines - metabolism</subject><subject>Triazines - pharmacology</subject><issn>0264-6021</issn><issn>1470-8728</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1u1TAQhS0EorctK_bISyQUajtO4myQyhUFqkpsurccZ3xjSOzgcSryCjw16Q9VuxjNSPPNmSMdQt5y9pEzKc4-7y8F4w3jonlBdlw2rFCNUC_JjolaFjUT_IgcI_5kjEsm2WtyJFSpeC3rHfl7Hsy4okcaHZ2HiFv5ENFn3wMti18-GATqw-A7n2NC2q20iznHqVhmCiPYnGIocjIBHSTae8Rovck-BjqsfYoHCGc9LBmSXyYKf-xgwgHoZBApznf3E-S0npJXzowIbx76Cbm--HK9_1Zc_fj6fX9-VdjNdC5AdGAkqE5Y1dZGcuhAiap1fVeVqt3mtgRb9X3rmKvBMWCmdIzVqoRGqfKEfLqXnZdugt5C2LyPek5-MmnV0Xj9fBP8oA_xRleVlJzdCrx_EEjx9wKY9eTRwjiaAHFBzZWSSolGiA39cI_aFBETuMc3nOnb8PST8Db63VNnj-z_tMp_VZaaqg</recordid><startdate>20170601</startdate><enddate>20170601</enddate><creator>Masson, Glenn R</creator><creator>Maslen, Sarah L</creator><creator>Williams, Roger L</creator><general>Portland Press 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>20170601</creationdate><title>Analysis of phosphoinositide 3-kinase inhibitors by bottom-up electron-transfer dissociation hydrogen/deuterium exchange mass spectrometry</title><author>Masson, Glenn R ; Maslen, Sarah L ; Williams, Roger L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c381t-e2bea4e8b2c896a41ebe8259fdb5389e8293ec5dd9f0f6ef0e0a3f00683e7883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - metabolism</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Binding Sites</topic><topic>Class I Phosphatidylinositol 3-Kinases</topic><topic>Class Ia Phosphatidylinositol 3-Kinase - chemistry</topic><topic>Class Ia Phosphatidylinositol 3-Kinase - genetics</topic><topic>Class Ia Phosphatidylinositol 3-Kinase - metabolism</topic><topic>Deuterium Exchange Measurement</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Electron Transport</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Indazoles - chemistry</topic><topic>Indazoles - metabolism</topic><topic>Indazoles - pharmacology</topic><topic>Models, Molecular</topic><topic>Molecular Weight</topic><topic>Oligonucleotides - antagonists & inhibitors</topic><topic>Oligonucleotides - chemistry</topic><topic>Oligonucleotides - genetics</topic><topic>Oligonucleotides - metabolism</topic><topic>Peptide Fragments - antagonists & inhibitors</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptide Fragments - genetics</topic><topic>Peptide Fragments - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - chemistry</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoinositide-3 Kinase Inhibitors</topic><topic>Protein Conformation</topic><topic>Purines - chemistry</topic><topic>Purines - metabolism</topic><topic>Purines - pharmacology</topic><topic>Pyridazines</topic><topic>Quinazolinones - chemistry</topic><topic>Quinazolinones - metabolism</topic><topic>Quinazolinones - pharmacology</topic><topic>Quinolines - chemistry</topic><topic>Quinolines - metabolism</topic><topic>Quinolines - pharmacology</topic><topic>Recombinant Fusion Proteins - chemistry</topic><topic>Recombinant Fusion Proteins - metabolism</topic><topic>Reproducibility of Results</topic><topic>Signal Processing, Computer-Assisted</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - metabolism</topic><topic>Sulfonamides - pharmacology</topic><topic>Tandem Mass Spectrometry</topic><topic>Triazines - chemistry</topic><topic>Triazines - metabolism</topic><topic>Triazines - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Masson, Glenn R</creatorcontrib><creatorcontrib>Maslen, Sarah L</creatorcontrib><creatorcontrib>Williams, Roger L</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>Biochemical journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Masson, Glenn R</au><au>Maslen, Sarah L</au><au>Williams, Roger L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analysis of phosphoinositide 3-kinase inhibitors by bottom-up electron-transfer dissociation hydrogen/deuterium exchange mass spectrometry</atitle><jtitle>Biochemical journal</jtitle><addtitle>Biochem J</addtitle><date>2017-06-01</date><risdate>2017</risdate><volume>474</volume><issue>11</issue><spage>1867</spage><epage>1877</epage><pages>1867-1877</pages><issn>0264-6021</issn><eissn>1470-8728</eissn><abstract>Until recently, one of the major limitations of hydrogen/deuterium exchange mass spectrometry (HDX-MS) was the peptide-level resolution afforded by proteolytic digestion. This limitation can be selectively overcome through the use of electron-transfer dissociation to fragment peptides in a manner that allows the retention of the deuterium signal to produce hydrogen/deuterium exchange tandem mass spectrometry (HDX-MS/MS). Here, we describe the application of HDX-MS/MS to structurally screen inhibitors of the oncogene phosphoinositide 3-kinase catalytic p110α subunit. HDX-MS/MS analysis is able to discern a conserved mechanism of inhibition common to a range of inhibitors. Owing to the relatively minor amounts of protein required, this technique may be utilised in pharmaceutical development for screening potential therapeutics.</abstract><cop>England</cop><pub>Portland Press Ltd</pub><pmid>28381646</pmid><doi>10.1042/BCJ20170127</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antineoplastic Agents - chemistry Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Binding Sites Class I Phosphatidylinositol 3-Kinases Class Ia Phosphatidylinositol 3-Kinase - chemistry Class Ia Phosphatidylinositol 3-Kinase - genetics Class Ia Phosphatidylinositol 3-Kinase - metabolism Deuterium Exchange Measurement Drug Evaluation, Preclinical - methods Electron Transport Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Humans Indazoles - chemistry Indazoles - metabolism Indazoles - pharmacology Models, Molecular Molecular Weight Oligonucleotides - antagonists & inhibitors Oligonucleotides - chemistry Oligonucleotides - genetics Oligonucleotides - metabolism Peptide Fragments - antagonists & inhibitors Peptide Fragments - chemistry Peptide Fragments - genetics Peptide Fragments - metabolism Phosphatidylinositol 3-Kinases - chemistry Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Phosphoinositide-3 Kinase Inhibitors Protein Conformation Purines - chemistry Purines - metabolism Purines - pharmacology Pyridazines Quinazolinones - chemistry Quinazolinones - metabolism Quinazolinones - pharmacology Quinolines - chemistry Quinolines - metabolism Quinolines - pharmacology Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - metabolism Reproducibility of Results Signal Processing, Computer-Assisted Sulfonamides - chemistry Sulfonamides - metabolism Sulfonamides - pharmacology Tandem Mass Spectrometry Triazines - chemistry Triazines - metabolism Triazines - pharmacology |
| title | Analysis of phosphoinositide 3-kinase inhibitors by bottom-up electron-transfer dissociation hydrogen/deuterium exchange mass spectrometry |
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