PfMDR1: mechanisms of transport modulation by functional polymorphisms
ATP-Binding Cassette (ABC) transporters are efflux pumps frequently associated with multidrug resistance in many biological systems, including malaria. Antimalarial drug-resistance involves an ABC transporter, PfMDR1, a homologue of P-glycoprotein in humans. Twenty years of research have shown that...
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| Veröffentlicht in: | PloS one 2011-09, Vol.6 (9), p.e23875-e23875 |
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| description | ATP-Binding Cassette (ABC) transporters are efflux pumps frequently associated with multidrug resistance in many biological systems, including malaria. Antimalarial drug-resistance involves an ABC transporter, PfMDR1, a homologue of P-glycoprotein in humans. Twenty years of research have shown that several single nucleotide polymorphisms in pfmdr1 modulate in vivo and/or in vitro drug susceptibility. The underlying physiological mechanism of the effect of these mutations remains unclear. Here we develop structural models for PfMDR1 in different predicted conformations, enabling the study of transporter motion. Such analysis of functional polymorphisms allows determination of their potential role in transport and resistance. The bacterial MsbA ABC pump is a PfMDR1 homologue. MsbA crystals in different conformations were used to create PfMDR1 models with Modeller software. Sequences were aligned with ClustalW and analysed by Ali2D revealing a high level of secondary structure conservation. To validate a potential drug binding pocket we performed antimalarial docking simulations. Using aminoquinoline as probe drugs in PfMDR1 mutated parasites we evaluated the physiology underlying the mechanisms of resistance mediated by PfMDR1 polymorphisms. We focused on the analysis of well known functional polymorphisms in PfMDR1 amino acid residues 86, 184, 1034, 1042 and 1246. Our structural analysis suggested the existence of two different biophysical mechanisms of PfMDR1 drug resistance modulation. Polymorphisms in residues 86/184/1246 act by internal allosteric modulation and residues 1034 and 1042 interact directly in a drug pocket. Parasites containing mutated PfMDR1 variants had a significant altered aminoquinoline susceptibility that appears to be dependent on the aminoquinoline lipophobicity characteristics as well as vacuolar efflux by PfCRT. We previously described the in vivo selection of PfMDR1 polymorphisms under antimalarial drug pressure. Now, together with recent PfMDR1 functional reports, we contribute to the understanding of the specific structural role of these polymorphisms in parasite antimalarial drug response. |
| doi_str_mv | 10.1371/journal.pone.0023875 |
| format | Article |
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M.</contributor><creatorcontrib>Ferreira, Pedro Eduardo ; Holmgren, Gabrielle ; Veiga, Maria Isabel ; Uhlén, Per ; Kaneko, Akira ; Gil, José Pedro ; Costa, Fabio T. M.</creatorcontrib><description>ATP-Binding Cassette (ABC) transporters are efflux pumps frequently associated with multidrug resistance in many biological systems, including malaria. Antimalarial drug-resistance involves an ABC transporter, PfMDR1, a homologue of P-glycoprotein in humans. Twenty years of research have shown that several single nucleotide polymorphisms in pfmdr1 modulate in vivo and/or in vitro drug susceptibility. The underlying physiological mechanism of the effect of these mutations remains unclear. Here we develop structural models for PfMDR1 in different predicted conformations, enabling the study of transporter motion. Such analysis of functional polymorphisms allows determination of their potential role in transport and resistance. The bacterial MsbA ABC pump is a PfMDR1 homologue. MsbA crystals in different conformations were used to create PfMDR1 models with Modeller software. Sequences were aligned with ClustalW and analysed by Ali2D revealing a high level of secondary structure conservation. To validate a potential drug binding pocket we performed antimalarial docking simulations. Using aminoquinoline as probe drugs in PfMDR1 mutated parasites we evaluated the physiology underlying the mechanisms of resistance mediated by PfMDR1 polymorphisms. We focused on the analysis of well known functional polymorphisms in PfMDR1 amino acid residues 86, 184, 1034, 1042 and 1246. Our structural analysis suggested the existence of two different biophysical mechanisms of PfMDR1 drug resistance modulation. Polymorphisms in residues 86/184/1246 act by internal allosteric modulation and residues 1034 and 1042 interact directly in a drug pocket. Parasites containing mutated PfMDR1 variants had a significant altered aminoquinoline susceptibility that appears to be dependent on the aminoquinoline lipophobicity characteristics as well as vacuolar efflux by PfCRT. We previously described the in vivo selection of PfMDR1 polymorphisms under antimalarial drug pressure. Now, together with recent PfMDR1 functional reports, we contribute to the understanding of the specific structural role of these polymorphisms in parasite antimalarial drug response.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0023875</identifier><identifier>PMID: 21912647</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>ABC transporter ; Adenosine triphosphate ; Algorithms ; Allosteric properties ; Amino acids ; Analysis ; Antimalarials - metabolism ; Antimalarials - pharmacology ; ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry ; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; Bacteria ; Binding ; Binding Sites ; Bioengineering ; Bioinformatics ; Biological Transport ; Biology ; Biophysics ; Biotechnology ; Chemotherapy ; Computer Science ; Computer simulation ; Conservation ; Crystallography ; Crystals ; Docking ; Drug resistance ; Drug Resistance - genetics ; Drugs ; Efflux ; Electric properties ; Enzymes ; Genetic aspects ; Glycoproteins ; Homology ; Humans ; Ligands ; Malaria ; Mammals ; Medicin och hälsovetenskap ; Medicine ; Microbial drug resistance ; Models, Molecular ; Modulation ; Multidrug resistance ; Mutation ; P-Glycoprotein ; Parasites ; Physiological aspects ; Physiological effects ; Plasmodium falciparum - drug effects ; Plasmodium falciparum - genetics ; Plasmodium falciparum - metabolism ; Polymorphism, Single Nucleotide ; Protein Conformation ; Protein structure ; Proteins ; Protozoan Proteins - chemistry ; Protozoan Proteins - genetics ; Protozoan Proteins - metabolism ; Residues ; Secondary structure ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Structural analysis ; Structural models ; Transport ; Vector-borne diseases</subject><ispartof>PloS one, 2011-09, Vol.6 (9), p.e23875-e23875</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Ferreira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Ferreira et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c878t-da574cff2a74a852a9712c127b1dfcabc0e2a96495e738d8b60a40da4cb20bee3</citedby><cites>FETCH-LOGICAL-c878t-da574cff2a74a852a9712c127b1dfcabc0e2a96495e738d8b60a40da4cb20bee3</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/PMC3164660/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164660/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,552,727,780,784,864,885,2100,2926,23864,27922,27923,53789,53791,79370,79371</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21912647$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:123215671$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><contributor>Costa, Fabio T. M.</contributor><creatorcontrib>Ferreira, Pedro Eduardo</creatorcontrib><creatorcontrib>Holmgren, Gabrielle</creatorcontrib><creatorcontrib>Veiga, Maria Isabel</creatorcontrib><creatorcontrib>Uhlén, Per</creatorcontrib><creatorcontrib>Kaneko, Akira</creatorcontrib><creatorcontrib>Gil, José Pedro</creatorcontrib><title>PfMDR1: mechanisms of transport modulation by functional polymorphisms</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>ATP-Binding Cassette (ABC) transporters are efflux pumps frequently associated with multidrug resistance in many biological systems, including malaria. Antimalarial drug-resistance involves an ABC transporter, PfMDR1, a homologue of P-glycoprotein in humans. Twenty years of research have shown that several single nucleotide polymorphisms in pfmdr1 modulate in vivo and/or in vitro drug susceptibility. The underlying physiological mechanism of the effect of these mutations remains unclear. Here we develop structural models for PfMDR1 in different predicted conformations, enabling the study of transporter motion. Such analysis of functional polymorphisms allows determination of their potential role in transport and resistance. The bacterial MsbA ABC pump is a PfMDR1 homologue. MsbA crystals in different conformations were used to create PfMDR1 models with Modeller software. Sequences were aligned with ClustalW and analysed by Ali2D revealing a high level of secondary structure conservation. To validate a potential drug binding pocket we performed antimalarial docking simulations. Using aminoquinoline as probe drugs in PfMDR1 mutated parasites we evaluated the physiology underlying the mechanisms of resistance mediated by PfMDR1 polymorphisms. We focused on the analysis of well known functional polymorphisms in PfMDR1 amino acid residues 86, 184, 1034, 1042 and 1246. Our structural analysis suggested the existence of two different biophysical mechanisms of PfMDR1 drug resistance modulation. Polymorphisms in residues 86/184/1246 act by internal allosteric modulation and residues 1034 and 1042 interact directly in a drug pocket. Parasites containing mutated PfMDR1 variants had a significant altered aminoquinoline susceptibility that appears to be dependent on the aminoquinoline lipophobicity characteristics as well as vacuolar efflux by PfCRT. We previously described the in vivo selection of PfMDR1 polymorphisms under antimalarial drug pressure. Now, together with recent PfMDR1 functional reports, we contribute to the understanding of the specific structural role of these polymorphisms in parasite antimalarial drug response.</description><subject>ABC transporter</subject><subject>Adenosine triphosphate</subject><subject>Algorithms</subject><subject>Allosteric properties</subject><subject>Amino acids</subject><subject>Analysis</subject><subject>Antimalarials - metabolism</subject><subject>Antimalarials - pharmacology</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - genetics</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</subject><subject>Bacteria</subject><subject>Binding</subject><subject>Binding Sites</subject><subject>Bioengineering</subject><subject>Bioinformatics</subject><subject>Biological Transport</subject><subject>Biology</subject><subject>Biophysics</subject><subject>Biotechnology</subject><subject>Chemotherapy</subject><subject>Computer Science</subject><subject>Computer simulation</subject><subject>Conservation</subject><subject>Crystallography</subject><subject>Crystals</subject><subject>Docking</subject><subject>Drug resistance</subject><subject>Drug Resistance - genetics</subject><subject>Drugs</subject><subject>Efflux</subject><subject>Electric properties</subject><subject>Enzymes</subject><subject>Genetic aspects</subject><subject>Glycoproteins</subject><subject>Homology</subject><subject>Humans</subject><subject>Ligands</subject><subject>Malaria</subject><subject>Mammals</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicine</subject><subject>Microbial drug resistance</subject><subject>Models, Molecular</subject><subject>Modulation</subject><subject>Multidrug resistance</subject><subject>Mutation</subject><subject>P-Glycoprotein</subject><subject>Parasites</subject><subject>Physiological aspects</subject><subject>Physiological effects</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Plasmodium falciparum - genetics</subject><subject>Plasmodium falciparum - metabolism</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein Conformation</subject><subject>Protein structure</subject><subject>Proteins</subject><subject>Protozoan Proteins - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ferreira, Pedro Eduardo</au><au>Holmgren, Gabrielle</au><au>Veiga, Maria Isabel</au><au>Uhlén, Per</au><au>Kaneko, Akira</au><au>Gil, José Pedro</au><au>Costa, Fabio T. M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PfMDR1: mechanisms of transport modulation by functional polymorphisms</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-09-01</date><risdate>2011</risdate><volume>6</volume><issue>9</issue><spage>e23875</spage><epage>e23875</epage><pages>e23875-e23875</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>ATP-Binding Cassette (ABC) transporters are efflux pumps frequently associated with multidrug resistance in many biological systems, including malaria. Antimalarial drug-resistance involves an ABC transporter, PfMDR1, a homologue of P-glycoprotein in humans. Twenty years of research have shown that several single nucleotide polymorphisms in pfmdr1 modulate in vivo and/or in vitro drug susceptibility. The underlying physiological mechanism of the effect of these mutations remains unclear. Here we develop structural models for PfMDR1 in different predicted conformations, enabling the study of transporter motion. Such analysis of functional polymorphisms allows determination of their potential role in transport and resistance. The bacterial MsbA ABC pump is a PfMDR1 homologue. MsbA crystals in different conformations were used to create PfMDR1 models with Modeller software. Sequences were aligned with ClustalW and analysed by Ali2D revealing a high level of secondary structure conservation. To validate a potential drug binding pocket we performed antimalarial docking simulations. Using aminoquinoline as probe drugs in PfMDR1 mutated parasites we evaluated the physiology underlying the mechanisms of resistance mediated by PfMDR1 polymorphisms. We focused on the analysis of well known functional polymorphisms in PfMDR1 amino acid residues 86, 184, 1034, 1042 and 1246. Our structural analysis suggested the existence of two different biophysical mechanisms of PfMDR1 drug resistance modulation. Polymorphisms in residues 86/184/1246 act by internal allosteric modulation and residues 1034 and 1042 interact directly in a drug pocket. Parasites containing mutated PfMDR1 variants had a significant altered aminoquinoline susceptibility that appears to be dependent on the aminoquinoline lipophobicity characteristics as well as vacuolar efflux by PfCRT. We previously described the in vivo selection of PfMDR1 polymorphisms under antimalarial drug pressure. Now, together with recent PfMDR1 functional reports, we contribute to the understanding of the specific structural role of these polymorphisms in parasite antimalarial drug response.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21912647</pmid><doi>10.1371/journal.pone.0023875</doi><tpages>e23875</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-09, Vol.6 (9), p.e23875-e23875 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1309033502 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; SWEPUB Freely available online; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | ABC transporter Adenosine triphosphate Algorithms Allosteric properties Amino acids Analysis Antimalarials - metabolism Antimalarials - pharmacology ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry ATP-Binding Cassette, Sub-Family B, Member 1 - genetics ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Bacteria Binding Binding Sites Bioengineering Bioinformatics Biological Transport Biology Biophysics Biotechnology Chemotherapy Computer Science Computer simulation Conservation Crystallography Crystals Docking Drug resistance Drug Resistance - genetics Drugs Efflux Electric properties Enzymes Genetic aspects Glycoproteins Homology Humans Ligands Malaria Mammals Medicin och hälsovetenskap Medicine Microbial drug resistance Models, Molecular Modulation Multidrug resistance Mutation P-Glycoprotein Parasites Physiological aspects Physiological effects Plasmodium falciparum - drug effects Plasmodium falciparum - genetics Plasmodium falciparum - metabolism Polymorphism, Single Nucleotide Protein Conformation Protein structure Proteins Protozoan Proteins - chemistry Protozoan Proteins - genetics Protozoan Proteins - metabolism Residues Secondary structure Single nucleotide polymorphisms Single-nucleotide polymorphism Structural analysis Structural models Transport Vector-borne diseases |
| title | PfMDR1: mechanisms of transport modulation by functional polymorphisms |
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