Allosteric Role of Substrate Occupancy Toward the Alignment of P-glycoprotein Nucleotide Binding Domains.

ABSTRACT: P-glycoprotein (Pgp) is an ATP-binding cassette transporter that eliminates toxins from the cell but causes multidrug resistance in chemotherapies. The crystal structures of Pgp revealed drug-like compounds bound to an inward-facing conformation in which the energy-harnessing nucleotide binding domains (NBDs) were widely separated with no interfacial interaction. Following drug binding, inward-facing Pgp must transition to an NBD dimer conformation to achieve ATP binding and hydrolysis at canonical sites defined by both halves of the interface. However, given the high degree of flexibility shown for this transporter, it is difficult to envision how NBDs overcome entropic considerations for achieving proper alignment in order to form the canonical ATP binding site. We explored the hypothesi

SUBMITTER: Pan L 

PROVIDER: S-EPMC6168518 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature