Drug Binding Sites on P-Glycoprotein Are Altered by ATP Binding Prior to Nucleotide Hydrolysis†

Biochemistry ◽  
2000 ◽  
Vol 39 (39) ◽  
pp. 11901-11906 ◽  
Author(s):  
Catherine Martin ◽  
Georgina Berridge ◽  
Prakash Mistry ◽  
Christopher Higgins ◽  
Peter Charlton ◽  
...  
Keyword(s):  
Binding Sites ◽  
Drug Binding ◽  
Atp Binding ◽  
Nucleotide Hydrolysis ◽  
P Glycoprotein ◽  
Drug Binding Sites

scholarly journals Novel features in the structure of P-glycoprotein (ABCB1) in the post-hydrolytic state as determined at 7.9Å resolution

2018 ◽  
Author(s):  
Nopnithi Thonghin ◽  
Richard F. Collins ◽  
Alessandro Barbieri ◽  
Talha Shafi ◽  
Alistair Siebert ◽  
...  
Keyword(s):  
Binding Sites ◽  
Drug Binding ◽  
Multi Drug Resistance ◽  
Binding Domains ◽  
Atp Binding Cassette Transporter ◽  
P Glycoprotein ◽  
Head Groups ◽  
Related Drug ◽  
Drug Binding Sites

AbstractP-glycoprotein (ABCB1) is a ATP-binding cassette transporter that plays an important role in the removal of drugs and xenobiotic compounds from the cell. It is also associated with multi-drug resistance in cancer. Here we report novel features of the cryo-EM-derived structure of P-glycoprotein in the post-hydrolytic state: The cytosolic nucleotide-binding domains (NBDs) are separated despite ADP remaining bound to the NBDs. Gaps in the TMDs that connect to the inner hydrophilic cavity are back-filled by detergent head-groups from the annular detergent micelle and are close to two regions predicted to delineate two pseudo-symmetry-related drug-binding sites. In this conformation, the (newly-resolved) N-terminal extension, NBD-TMD linker region and gap-filling detergents all appear to impede NBD dimerisation. We propose a model for the mechanism of action of the exporter where ATP will be bound to the protein for most of the time, consistent with the high physiological ATP concentrationsin vivo.

Communication between Multiple Drug Binding Sites on P-glycoprotein

2000 ◽  
Vol 58 (3) ◽  
pp. 624-632 ◽  
Author(s):  
Catherine Martin ◽  
Georgina Berridge ◽  
Christopher F. Higgins ◽  
Prakash Mistry ◽  
Peter Charlton ◽  
...  
Keyword(s):  
Binding Sites ◽  
Drug Binding ◽  
Multiple Drug ◽  
P Glycoprotein ◽  
Drug Binding Sites

A New Paclitaxel Photoaffinity Analog with a 3-(4-Benzoylphenyl)propanoyl Probe for Characterization of Drug-Binding Sites on Tubulin and P-Glycoprotein

1995 ◽  
Vol 38 (20) ◽  
pp. 3891-3894 ◽  
Author(s):  
Iwao Ojima ◽  
Olivier Duclos ◽  
Gyorgy Dorman ◽  
Bruno Simonot ◽  
Glenn D. Prestwich ◽  
...  
Keyword(s):  
Binding Sites ◽  
Drug Binding ◽  
P Glycoprotein ◽  
Drug Binding Sites
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