Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation - PubMed (original) (raw)

. 2018 Feb 23;359(6378):915-919.

doi: 10.1126/science.aar7389. Epub 2018 Jan 25.

Affiliations

• PMID: 29371429
• DOI: 10.1126/science.aar7389

Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation

Youngjin Kim et al. Science. 2018.

Abstract

The multidrug transporter permeability (P)-glycoprotein is an adenosine triphosphate (ATP)-binding cassette exporter responsible for clinical resistance to chemotherapy. P-glycoprotein extrudes toxic molecules and drugs from cells through ATP-powered conformational changes. Despite decades of effort, only the structures of the inward-facing conformation of P-glycoprotein are available. Here we present the structure of human P-glycoprotein in the outward-facing conformation, determined by cryo-electron microscopy at 3.4-angstrom resolution. The two nucleotide-binding domains form a closed dimer occluding two ATP molecules. The drug-binding cavity observed in the inward-facing structures is reorientated toward the extracellular space and compressed to preclude substrate binding. This observation indicates that ATP binding, not hydrolysis, promotes substrate release. The structure evokes a model in which the dynamic nature of P-glycoprotein enables translocation of a large variety of substrates.

Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PubMed Disclaimer

Similar articles

• Cryo-EM Analysis of the Conformational Landscape of Human P-glycoprotein (ABCB1) During its Catalytic Cycle.
  Frank GA, Shukla S, Rao P, Borgnia MJ, Bartesaghi A, Merk A, Mobin A, Esser L, Earl LA, Gottesman MM, Xia D, Ambudkar SV, Subramaniam S. Frank GA, et al. Mol Pharmacol. 2016 Jul;90(1):35-41. doi: 10.1124/mol.116.104190. Epub 2016 May 11. Mol Pharmacol. 2016. PMID: 27190212 Free PMC article.
• In vivo FRET analyses reveal a role of ATP hydrolysis-associated conformational changes in human P-glycoprotein.
  Futamata R, Ogasawara F, Ichikawa T, Kodan A, Kimura Y, Kioka N, Ueda K. Futamata R, et al. J Biol Chem. 2020 Apr 10;295(15):5002-5011. doi: 10.1074/jbc.RA119.012042. Epub 2020 Feb 28. J Biol Chem. 2020. PMID: 32111736 Free PMC article.
• Inward- and outward-facing X-ray crystal structures of homodimeric P-glycoprotein CmABCB1.
  Kodan A, Yamaguchi T, Nakatsu T, Matsuoka K, Kimura Y, Ueda K, Kato H. Kodan A, et al. Nat Commun. 2019 Jan 8;10(1):88. doi: 10.1038/s41467-018-08007-x. Nat Commun. 2019. PMID: 30622258 Free PMC article.
• Molecular basis of multidrug transport by ATP-binding cassette transporters: a proposed two-cylinder engine model.
  van Veen HW, Higgins CF, Konings WN. van Veen HW, et al. J Mol Microbiol Biotechnol. 2001 Apr;3(2):185-92. J Mol Microbiol Biotechnol. 2001. PMID: 11321572 Review.
• Structure and mechanism of ABC transporter proteins.
  Hollenstein K, Dawson RJ, Locher KP. Hollenstein K, et al. Curr Opin Struct Biol. 2007 Aug;17(4):412-8. doi: 10.1016/j.sbi.2007.07.003. Epub 2007 Aug 27. Curr Opin Struct Biol. 2007. PMID: 17723295 Review.

Cited by

• Structural identification of a selectivity filter in CFTR.
  Levring J, Chen J. Levring J, et al. Proc Natl Acad Sci U S A. 2024 Feb 27;121(9):e2316673121. doi: 10.1073/pnas.2316673121. Epub 2024 Feb 21. Proc Natl Acad Sci U S A. 2024. PMID: 38381791 Free PMC article.
• Structure-based discovery of novel P-glycoprotein inhibitors targeting the nucleotide binding domains.
  Moesgaard L, Pedersen ML, Uhd Nielsen C, Kongsted J. Moesgaard L, et al. Sci Rep. 2023 Dec 1;13(1):21217. doi: 10.1038/s41598-023-48281-4. Sci Rep. 2023. PMID: 38040777 Free PMC article.
• Ivacaftor-Mediated Potentiation of ABCB4 Missense Mutations Affecting Critical Motifs of the NBDs: Repositioning Perspectives for Hepatobiliary Diseases.
  Delaunay JL, Elbahnsi A, Bruneau A, Madry C, Durand-Schneider AM, Stary A, Housset C, Gautheron J, Callebaut I, Aït-Slimane T. Delaunay JL, et al. Int J Mol Sci. 2023 Jan 8;24(2):1236. doi: 10.3390/ijms24021236. Int J Mol Sci. 2023. PMID: 36674751 Free PMC article.
• Pharmacogenomic network analysis of the gene-drug interaction landscape underlying drug disposition.
  Zhou Y, Lauschke VM. Zhou Y, et al. Comput Struct Biotechnol J. 2019 Dec 5;18:52-58. doi: 10.1016/j.csbj.2019.11.010. eCollection 2020. Comput Struct Biotechnol J. 2019. PMID: 31890144 Free PMC article.
• An Update on the Anticancer Activity of Xanthone Derivatives: A Review.
  Kurniawan YS, Priyangga KTA, Jumina, Pranowo HD, Sholikhah EN, Zulkarnain AK, Fatimi HA, Julianus J. Kurniawan YS, et al. Pharmaceuticals (Basel). 2021 Nov 11;14(11):1144. doi: 10.3390/ph14111144. Pharmaceuticals (Basel). 2021. PMID: 34832926 Free PMC article. Review.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Atypon
  • Ovid Technologies, Inc.

• Other Literature Sources

  • H1 Connect
  • The Lens - Patent Citations Database
  • scite Smart Citations

• Molecular Biology Databases

  • Guide to Pharmacology
  • NIAID Data Ecosystem - Find datasets on Infectious and Immune-mediated Diseases