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Cryo-EM Analysis of the Conformational Landscape of Human P-glycoprotein (ABCB1) During its Catalytic Cycle.

Publication ,  Journal Article
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
Published in: Mol Pharmacol
July 2016

The multidrug transporter P-glycoprotein (P-gp, ABCB1) is an ATP-dependent pump that mediates the efflux of structurally diverse drugs and xenobiotics across cell membranes, affecting drug pharmacokinetics and contributing to the development of multidrug resistance. Structural information about the conformational changes in human P-gp during the ATP hydrolysis cycle has not been directly demonstrated, although mechanistic information has been inferred from biochemical and biophysical studies conducted with P-gp and its orthologs, or from structures of other ATP-binding cassette transporters. Using single-particle cryo-electron microscopy, we report the surprising discovery that, in the absence of the transport substrate and nucleotides, human P-gp can exist in both open [nucleotide binding domains (NBDs) apart; inward-facing] and closed (NBDs close; outward-facing) conformations. We also probe conformational states of human P-gp during the catalytic cycle, and demonstrate that, following ATP hydrolysis, P-gp transitions through a complete closed conformation to a complete open conformation in the presence of ADP.

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Published In

Mol Pharmacol

DOI

EISSN

1521-0111

Publication Date

July 2016

Volume

90

Issue

1

Start / End Page

35 / 41

Location

United States

Related Subject Headings

  • Protein Conformation
  • Pharmacology & Pharmacy
  • Models, Biological
  • Hydrolysis
  • Humans
  • Crystallography, X-Ray
  • Cryoelectron Microscopy
  • Biocatalysis
  • Adenosine Triphosphate
  • Adenosine Diphosphate
 

Citation

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Frank, G. A., Shukla, S., Rao, P., Borgnia, M. J., Bartesaghi, A., Merk, A., … Subramaniam, S. (2016). Cryo-EM Analysis of the Conformational Landscape of Human P-glycoprotein (ABCB1) During its Catalytic Cycle. Mol Pharmacol, 90(1), 35–41. https://doi.org/10.1124/mol.116.104190
Frank, Gabriel A., Suneet Shukla, Prashant Rao, Mario J. Borgnia, Alberto Bartesaghi, Alan Merk, Aerfa Mobin, et al. “Cryo-EM Analysis of the Conformational Landscape of Human P-glycoprotein (ABCB1) During its Catalytic Cycle.Mol Pharmacol 90, no. 1 (July 2016): 35–41. https://doi.org/10.1124/mol.116.104190.
Frank GA, Shukla S, Rao P, Borgnia MJ, Bartesaghi A, Merk A, et al. Cryo-EM Analysis of the Conformational Landscape of Human P-glycoprotein (ABCB1) During its Catalytic Cycle. Mol Pharmacol. 2016 Jul;90(1):35–41.
Frank, Gabriel A., et al. “Cryo-EM Analysis of the Conformational Landscape of Human P-glycoprotein (ABCB1) During its Catalytic Cycle.Mol Pharmacol, vol. 90, no. 1, July 2016, pp. 35–41. Pubmed, doi:10.1124/mol.116.104190.
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. Cryo-EM Analysis of the Conformational Landscape of Human P-glycoprotein (ABCB1) During its Catalytic Cycle. Mol Pharmacol. 2016 Jul;90(1):35–41.
Journal cover image

Published In

Mol Pharmacol

DOI

EISSN

1521-0111

Publication Date

July 2016

Volume

90

Issue

1

Start / End Page

35 / 41

Location

United States

Related Subject Headings

  • Protein Conformation
  • Pharmacology & Pharmacy
  • Models, Biological
  • Hydrolysis
  • Humans
  • Crystallography, X-Ray
  • Cryoelectron Microscopy
  • Biocatalysis
  • Adenosine Triphosphate
  • Adenosine Diphosphate