The ABCG2 multidrug transporter is a pump gated by a valve and an extracellular lid.
Nat Commun
; 10(1): 5433, 2019 11 28.
Article
em En
| MEDLINE
| ID: mdl-31780715
ABSTRACT
The human ATP-binding cassette transporter ABCG2 is a key to anticancer resistance and physiological detoxification. However, the molecular mechanism of substrate transport remains enigmatic. A hydrophobic di-leucine motif in the ABCG2 core separates a large intracellular cavity from a smaller upper cavity. We show that the di-leucine motif acts as a valve that controls drug extrusion. Moreover, the extracellular structure engages the re-entry helix and all extracellular loops to form a roof architecture on top of the upper cavity. Disulfide bridges and a salt bridge limit roof flexibility, but provide a lid-like function to control drug release. We propose that drug translocation from the central to the upper cavities through the valve is driven by a squeezing motion, suggesting that ABCG2 operates similar to a peristaltic pump. Finally, the roof contains essential residues, offering therapeutic options to block ABCG2 by either targeting the valve or essential residues in the roof.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP
/
Proteínas de Neoplasias
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article