De novo macrocyclic peptides dissect energy coupling of a heterodimeric ABC transporter by multimode allosteric inhibition
ATP-binding cassette (ABC) transporters constitute the largest family of primary active transporters involved in a multitude of physiological processes and human diseases. Despite considerable efforts, it remains unclear how ABC transporters harness the chemical energy of ATP to drive substrate tran...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/67732 |
| _version_ | 1811201275859042304 |
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| author | Erich Stefan Richard Obexer Susanne Hofmann Khanh Vu Huu Yichao Huang Nina Morgner Hiroaki Suga Robert Tampé |
| author_facet | Erich Stefan Richard Obexer Susanne Hofmann Khanh Vu Huu Yichao Huang Nina Morgner Hiroaki Suga Robert Tampé |
| author_sort | Erich Stefan |
| collection | DOAJ |
| description | ATP-binding cassette (ABC) transporters constitute the largest family of primary active transporters involved in a multitude of physiological processes and human diseases. Despite considerable efforts, it remains unclear how ABC transporters harness the chemical energy of ATP to drive substrate transport across cell membranes. Here, by random nonstandard peptide integrated discovery (RaPID), we leveraged combinatorial macrocyclic peptides that target a heterodimeric ABC transport complex and explore fundamental principles of the substrate translocation cycle. High-affinity peptidic macrocycles bind conformationally selective and display potent multimode inhibitory effects. The macrocycles block the transporter either before or after unidirectional substrate export along a single conformational switch induced by ATP binding. Our study reveals mechanistic principles of ATP binding, conformational switching, and energy transduction for substrate transport of ABC export systems. We highlight the potential of de novo macrocycles as effective inhibitors for membrane proteins implicated in multidrug resistance, providing avenues for the next generation of pharmaceuticals. |
| first_indexed | 2024-04-12T02:19:22Z |
| format | Article |
| id | doaj.art-c60fc880ff0141849e077e85aa6c65b3 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:19:22Z |
| publishDate | 2021-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c60fc880ff0141849e077e85aa6c65b32022-12-22T03:52:11ZengeLife Sciences Publications LtdeLife2050-084X2021-04-011010.7554/eLife.67732De novo macrocyclic peptides dissect energy coupling of a heterodimeric ABC transporter by multimode allosteric inhibitionErich Stefan0Richard Obexer1Susanne Hofmann2Khanh Vu Huu3Yichao Huang4Nina Morgner5https://orcid.org/0000-0002-1872-490XHiroaki Suga6Robert Tampé7https://orcid.org/0000-0002-0403-2160Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Frankfurt, GermanyDepartment of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, JapanInstitute of Biochemistry, Biocenter, Goethe University Frankfurt, Frankfurt, GermanyInstitute of Physical and Theoretical Chemistry, Goethe University Frankfurt, Frankfurt, GermanyDepartment of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, JapanInstitute of Physical and Theoretical Chemistry, Goethe University Frankfurt, Frankfurt, GermanyDepartment of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, JapanInstitute of Biochemistry, Biocenter, Goethe University Frankfurt, Frankfurt, GermanyATP-binding cassette (ABC) transporters constitute the largest family of primary active transporters involved in a multitude of physiological processes and human diseases. Despite considerable efforts, it remains unclear how ABC transporters harness the chemical energy of ATP to drive substrate transport across cell membranes. Here, by random nonstandard peptide integrated discovery (RaPID), we leveraged combinatorial macrocyclic peptides that target a heterodimeric ABC transport complex and explore fundamental principles of the substrate translocation cycle. High-affinity peptidic macrocycles bind conformationally selective and display potent multimode inhibitory effects. The macrocycles block the transporter either before or after unidirectional substrate export along a single conformational switch induced by ATP binding. Our study reveals mechanistic principles of ATP binding, conformational switching, and energy transduction for substrate transport of ABC export systems. We highlight the potential of de novo macrocycles as effective inhibitors for membrane proteins implicated in multidrug resistance, providing avenues for the next generation of pharmaceuticals.https://elifesciences.org/articles/67732antibioticscombinatorial chemistryconformational dynamicsligand-protein interactionmembrane proteintransporter |
| spellingShingle | Erich Stefan Richard Obexer Susanne Hofmann Khanh Vu Huu Yichao Huang Nina Morgner Hiroaki Suga Robert Tampé De novo macrocyclic peptides dissect energy coupling of a heterodimeric ABC transporter by multimode allosteric inhibition eLife antibiotics combinatorial chemistry conformational dynamics ligand-protein interaction membrane protein transporter |
| title | De novo macrocyclic peptides dissect energy coupling of a heterodimeric ABC transporter by multimode allosteric inhibition |
| title_full | De novo macrocyclic peptides dissect energy coupling of a heterodimeric ABC transporter by multimode allosteric inhibition |
| title_fullStr | De novo macrocyclic peptides dissect energy coupling of a heterodimeric ABC transporter by multimode allosteric inhibition |
| title_full_unstemmed | De novo macrocyclic peptides dissect energy coupling of a heterodimeric ABC transporter by multimode allosteric inhibition |
| title_short | De novo macrocyclic peptides dissect energy coupling of a heterodimeric ABC transporter by multimode allosteric inhibition |
| title_sort | de novo macrocyclic peptides dissect energy coupling of a heterodimeric abc transporter by multimode allosteric inhibition |
| topic | antibiotics combinatorial chemistry conformational dynamics ligand-protein interaction membrane protein transporter |
| url | https://elifesciences.org/articles/67732 |
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