5NIV

Crystal structure of 5D3 Fab

Summary for 5NIV

• Entry DOI: 10.2210/pdb5niv/pdb
• Descriptor: Light chain of 5D3 Fab, Heavy chain of 5D3 Fab (3 entities in total)
• Functional Keywords: fab, abcg2, inhibitor, immune system
• Biological source: Mus musculus (House mouse); More
• Total number of polymer chains: 2
• Total formula weight: 47219.42

Authors

Manolaridis, I.,Locher, K.P. (deposition date: 2017-03-27, release date: 2017-06-07, Last modification date: 2024-01-17)

Primary citation

Taylor, N.M.I.,Manolaridis, I.,Jackson, S.M.,Kowal, J.,Stahlberg, H.,Locher, K.P.
Structure of the human multidrug transporter ABCG2.
Nature, 546:504-509, 2017

PubMed Abstract: ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance. Here we present the structure of human ABCG2 determined by cryo-electron microscopy, providing the first high-resolution insight into a human multidrug transporter. We visualize ABCG2 in complex with two antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. We observe two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional in vitro analyses, our results suggest a multidrug recognition and transport mechanism of ABCG2, rationalize disease-causing single nucleotide polymorphisms and the allosteric inhibition by the 5D3 antibody, and provide the structural basis of cholesterol recognition by other G-subfamily ABC transporters.

PubMed: 28554189
DOI: 10.1038/nature22345

Experimental method

X-RAY DIFFRACTION (1.498 Å)