Structural and evolutionary analyses of the Plasmodium falciparum chloroquine resistance transporter
Mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to several antimalarial drugs such as chloroquine (CQ) or piperaquine (PPQ), a partner molecule in current artemisinin-based combination therapies. As a member of the Drug/Metabolite Transporter (DMT)...
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| description | Mutations in the
Plasmodium falciparum
chloroquine resistance transporter (PfCRT) confer resistance to several antimalarial drugs such as chloroquine (CQ) or piperaquine (PPQ), a partner molecule in current artemisinin-based combination therapies. As a member of the Drug/Metabolite Transporter (DMT) superfamily, the vacuolar transporter PfCRT may translocate substrate molecule(s) across the membrane of the digestive vacuole (DV), a lysosome-like organelle. However, the physiological substrate(s), the transport mechanism and the functional regions of PfCRT remain to be fully characterized. Here, we hypothesized that identification of evolutionary conserved sites in a tertiary structural context could help locate putative functional regions of PfCRT. Hence, site-specific substitution rates were estimated over
Plasmodium
evolution at each amino acid sites, and the PfCRT tertiary structure was predicted in both inward-facing (open-to-vacuole) and occluded states through homology modeling using DMT template structures sharing |
| doi_str_mv | 10.1038/s41598-020-61181-1 |
| format | Article |
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Plasmodium falciparum
chloroquine resistance transporter (PfCRT) confer resistance to several antimalarial drugs such as chloroquine (CQ) or piperaquine (PPQ), a partner molecule in current artemisinin-based combination therapies. As a member of the Drug/Metabolite Transporter (DMT) superfamily, the vacuolar transporter PfCRT may translocate substrate molecule(s) across the membrane of the digestive vacuole (DV), a lysosome-like organelle. However, the physiological substrate(s), the transport mechanism and the functional regions of PfCRT remain to be fully characterized. Here, we hypothesized that identification of evolutionary conserved sites in a tertiary structural context could help locate putative functional regions of PfCRT. Hence, site-specific substitution rates were estimated over
Plasmodium
evolution at each amino acid sites, and the PfCRT tertiary structure was predicted in both inward-facing (open-to-vacuole) and occluded states through homology modeling using DMT template structures sharing <15% sequence identity with PfCRT. We found that the vacuolar-half and membrane-spanning domain (and especially the transmembrane helix 9) of PfCRT were more conserved, supporting that its physiological substrate is expelled out of the parasite DV. In the PfCRT occluded state, some evolutionary conserved sites, including positions related to drug resistance mutations, participate in a putative binding pocket located at the core of the PfCRT membrane-spanning domain. Through structural comparison with experimentally-characterized DMT transporters, we identified several conserved PfCRT amino acid sites located in this pocket as robust candidates for mediating substrate transport. Finally,
in silico
mutagenesis revealed that drug resistance mutations caused drastic changes in the electrostatic potential of the transporter vacuolar entry and pocket, facilitating the escape of protonated CQ and PPQ from the parasite DV.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-61181-1</identifier><identifier>PMID: 32179795</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/114/2410 ; 631/114/2411 ; 631/114/663 ; 631/114/739 ; 631/181/735 ; Amino acid substitution ; Amino acids ; Amino Acids - metabolism ; Antimalarials - pharmacology ; Artemisinin ; Chloroquine ; Chloroquine - pharmacology ; Drug resistance ; Drug Resistance - genetics ; Electrostatic properties ; Evolution, Molecular ; Evolutionary conservation ; Homology ; Humanities and Social Sciences ; Membrane Transport Proteins - chemistry ; Membrane Transport Proteins - genetics ; Metabolites ; multidisciplinary ; Mutagenesis ; Mutation ; Parasites ; Parasitic Sensitivity Tests ; Phylogeny ; Physiology ; Plasmodium falciparum ; Plasmodium falciparum - cytology ; Plasmodium falciparum - drug effects ; Plasmodium falciparum - genetics ; Plasmodium falciparum - metabolism ; Protein structure ; Protozoan Proteins - chemistry ; Protozoan Proteins - genetics ; Quinolines - pharmacology ; Science ; Science (multidisciplinary) ; Substrates ; Tertiary structure ; Vacuoles</subject><ispartof>Scientific reports, 2020-03, Vol.10 (1), p.4842, Article 4842</ispartof><rights>The Author(s) 2020</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-a3e324ec7bb458e02037504d9b379a3e9930f279a476f923dcd1e6935b3eb56c3</citedby><cites>FETCH-LOGICAL-c511t-a3e324ec7bb458e02037504d9b379a3e9930f279a476f923dcd1e6935b3eb56c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076037/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076037/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51554,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32179795$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Coppée, Romain</creatorcontrib><creatorcontrib>Sabbagh, Audrey</creatorcontrib><creatorcontrib>Clain, Jérôme</creatorcontrib><title>Structural and evolutionary analyses of the Plasmodium falciparum chloroquine resistance transporter</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Mutations in the
Plasmodium falciparum
chloroquine resistance transporter (PfCRT) confer resistance to several antimalarial drugs such as chloroquine (CQ) or piperaquine (PPQ), a partner molecule in current artemisinin-based combination therapies. As a member of the Drug/Metabolite Transporter (DMT) superfamily, the vacuolar transporter PfCRT may translocate substrate molecule(s) across the membrane of the digestive vacuole (DV), a lysosome-like organelle. However, the physiological substrate(s), the transport mechanism and the functional regions of PfCRT remain to be fully characterized. Here, we hypothesized that identification of evolutionary conserved sites in a tertiary structural context could help locate putative functional regions of PfCRT. Hence, site-specific substitution rates were estimated over
Plasmodium
evolution at each amino acid sites, and the PfCRT tertiary structure was predicted in both inward-facing (open-to-vacuole) and occluded states through homology modeling using DMT template structures sharing <15% sequence identity with PfCRT. We found that the vacuolar-half and membrane-spanning domain (and especially the transmembrane helix 9) of PfCRT were more conserved, supporting that its physiological substrate is expelled out of the parasite DV. In the PfCRT occluded state, some evolutionary conserved sites, including positions related to drug resistance mutations, participate in a putative binding pocket located at the core of the PfCRT membrane-spanning domain. Through structural comparison with experimentally-characterized DMT transporters, we identified several conserved PfCRT amino acid sites located in this pocket as robust candidates for mediating substrate transport. Finally,
in silico
mutagenesis revealed that drug resistance mutations caused drastic changes in the electrostatic potential of the transporter vacuolar entry and pocket, facilitating the escape of protonated CQ and PPQ from the parasite DV.</description><subject>631/114/2410</subject><subject>631/114/2411</subject><subject>631/114/663</subject><subject>631/114/739</subject><subject>631/181/735</subject><subject>Amino acid substitution</subject><subject>Amino acids</subject><subject>Amino Acids - metabolism</subject><subject>Antimalarials - pharmacology</subject><subject>Artemisinin</subject><subject>Chloroquine</subject><subject>Chloroquine - pharmacology</subject><subject>Drug resistance</subject><subject>Drug Resistance - genetics</subject><subject>Electrostatic properties</subject><subject>Evolution, Molecular</subject><subject>Evolutionary conservation</subject><subject>Homology</subject><subject>Humanities and Social Sciences</subject><subject>Membrane Transport Proteins - chemistry</subject><subject>Membrane Transport Proteins - genetics</subject><subject>Metabolites</subject><subject>multidisciplinary</subject><subject>Mutagenesis</subject><subject>Mutation</subject><subject>Parasites</subject><subject>Parasitic Sensitivity Tests</subject><subject>Phylogeny</subject><subject>Physiology</subject><subject>Plasmodium falciparum</subject><subject>Plasmodium falciparum - cytology</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Plasmodium falciparum - genetics</subject><subject>Plasmodium falciparum - metabolism</subject><subject>Protein structure</subject><subject>Protozoan Proteins - chemistry</subject><subject>Protozoan Proteins - genetics</subject><subject>Quinolines - pharmacology</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Substrates</subject><subject>Tertiary structure</subject><subject>Vacuoles</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9UV1LwzAUDaK4MfcHfJCCz9V8NM3yIsjwCwQF9Tmk6e3W0TUzSQf792Z2zvliXnLJPfece3IQOif4imA2ufYZ4XKSYorTnJAJSckRGlKc8ZQySo8P6gEae7_A8XAqMyJP0YBRIqSQfIjKt-A6Ezqnm0S3ZQJr23Shtq12m_igm40Hn9gqCXNIXhvtl7asu2VS6cbUK-1iaeaNdfazq1tIHPjaB90aSILTrV9ZF8CdoZOI9zDe3SP0cX_3Pn1Mn18enqa3z6nhhIRUM2A0AyOKIuMTiNaY4DgrZcGEjE0pGa5oLDORV5Ky0pQEcsl4waDguWEjdNPzrrpiCaWBNi7RqJWrl9GOsrpWfzttPVczu1YCizyKRYLLHcHWEPigFrZz8Re8okyIXDCcbVG0RxlnvXdQ7RUIVttwVB-Oig7UdziKxKGLw932Iz9RRADrAT622hm4X-1_aL8AEQydWw</recordid><startdate>20200316</startdate><enddate>20200316</enddate><creator>Coppée, Romain</creator><creator>Sabbagh, Audrey</creator><creator>Clain, Jérôme</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>5PM</scope></search><sort><creationdate>20200316</creationdate><title>Structural and evolutionary analyses of the Plasmodium falciparum chloroquine resistance transporter</title><author>Coppée, Romain ; 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Plasmodium falciparum
chloroquine resistance transporter (PfCRT) confer resistance to several antimalarial drugs such as chloroquine (CQ) or piperaquine (PPQ), a partner molecule in current artemisinin-based combination therapies. As a member of the Drug/Metabolite Transporter (DMT) superfamily, the vacuolar transporter PfCRT may translocate substrate molecule(s) across the membrane of the digestive vacuole (DV), a lysosome-like organelle. However, the physiological substrate(s), the transport mechanism and the functional regions of PfCRT remain to be fully characterized. Here, we hypothesized that identification of evolutionary conserved sites in a tertiary structural context could help locate putative functional regions of PfCRT. Hence, site-specific substitution rates were estimated over
Plasmodium
evolution at each amino acid sites, and the PfCRT tertiary structure was predicted in both inward-facing (open-to-vacuole) and occluded states through homology modeling using DMT template structures sharing <15% sequence identity with PfCRT. We found that the vacuolar-half and membrane-spanning domain (and especially the transmembrane helix 9) of PfCRT were more conserved, supporting that its physiological substrate is expelled out of the parasite DV. In the PfCRT occluded state, some evolutionary conserved sites, including positions related to drug resistance mutations, participate in a putative binding pocket located at the core of the PfCRT membrane-spanning domain. Through structural comparison with experimentally-characterized DMT transporters, we identified several conserved PfCRT amino acid sites located in this pocket as robust candidates for mediating substrate transport. Finally,
in silico
mutagenesis revealed that drug resistance mutations caused drastic changes in the electrostatic potential of the transporter vacuolar entry and pocket, facilitating the escape of protonated CQ and PPQ from the parasite DV.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32179795</pmid><doi>10.1038/s41598-020-61181-1</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 631/114/2410 631/114/2411 631/114/663 631/114/739 631/181/735 Amino acid substitution Amino acids Amino Acids - metabolism Antimalarials - pharmacology Artemisinin Chloroquine Chloroquine - pharmacology Drug resistance Drug Resistance - genetics Electrostatic properties Evolution, Molecular Evolutionary conservation Homology Humanities and Social Sciences Membrane Transport Proteins - chemistry Membrane Transport Proteins - genetics Metabolites multidisciplinary Mutagenesis Mutation Parasites Parasitic Sensitivity Tests Phylogeny Physiology Plasmodium falciparum Plasmodium falciparum - cytology Plasmodium falciparum - drug effects Plasmodium falciparum - genetics Plasmodium falciparum - metabolism Protein structure Protozoan Proteins - chemistry Protozoan Proteins - genetics Quinolines - pharmacology Science Science (multidisciplinary) Substrates Tertiary structure Vacuoles |
| title | Structural and evolutionary analyses of the Plasmodium falciparum chloroquine resistance transporter |
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