Outward-facing P-glycoprotein bound to drug displays nucleotide-dependent drug egress mechanism
Han, S. B.; Prince, S. M.; Warwicker, J.; Fan, H.
Show abstract
ABCB1/P-glycoprotein requires coordination between ligand movement in the trans-membrane cavity and ATP binding and hydrolysis at the nucleotide binding domains, yet the sequence of these events remains incompletely resolved. Here, atomistic simulations with paclitaxel and verapamil across outward facing P-glycoprotein ensembles in various nucleotide states were integrated with analysis of transmembrane domain contacts, geometric solvent/ligand pathways, extracellular gating distances, and nucleotide coordi-nation characterization. Collectively, our simulations delineate a mechanistic framework for P-glycoprotein in which ATP binding organizes an outward-facing ensemble and sequential hydrolysis at the two nucleotide-binding sites drives substrate progression toward egress. Asymmetry in the nucleotide state is correlated to distinct motions within the transmembrane domains, which suggests a possible transient extracellular gating mechanism that enables staged release and limits re-entry of the ligand. The resulting model connects nucleotide chemistry to transmembrane domain motions that regulate gate dynamics and may guide experiments and development of modulators for ABC exporter activity in physiological and pharmacological contexts.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Conformational flexibility Of A Highly Conserved Helix Controls Cryptic Pocket Formation In FtsZ 94%
- ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events 94%
- An intracellular pathway controlled by the N-terminus of the pump subunit inhibits the bacterial KdpFABC ion pump in high K+ conditions 94%
Similar papers in this journal
Similar papers in this journal
- MDPath: Unraveling Allosteric Communication Paths of Drug Targets through Molecular Dynamics Simulations 94%
- Unveiling G-Protein-Coupled Receptor Conformational Dynamics via Metadynamics Simulations and Markov State Models 94%
- Structural insights into ATP-sensitive potassium channel mechanics: a role of intrinsically disordered regions. 93%
Similar papers in this journal
- State-specific morphological deformations of the lipid bilayer explain mechanosensitive gating of MscS ion channels 94%
- Disease related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveals a path to selective inhibitors 93%
- Conserved allosteric inhibition mechanism in SLC1 transporters 93%
Similar papers in this journal
- Symmetry-adapted Markov state models of closing, opening, and desensitizing in α7 nicotinic acetylcholine receptors 95%
- Mechanistic basis of the dynamic response of TWIK1 ionic selectivity to pH 94%
- From head to tail - Atomistic mechanism of long-range coupling from the cytosolic sensor domain to the selectivity filter in TREK K2P channels 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.