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-Structure paper
Title | High-resolution structures of multiple 5-HTR-setron complexes reveal a novel mechanism of competitive inhibition. |
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Journal, issue, pages | Elife, Vol. 9, Year 2020 |
Publish date | Oct 16, 2020 |
Authors | Sandip Basak / Arvind Kumar / Steven Ramsey / Eric Gibbs / Abhijeet Kapoor / Marta Filizola / Sudha Chakrapani / |
PubMed Abstract | Serotonin receptors (5-HTR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea ...Serotonin receptors (5-HTR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HTR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HTR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HTR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition. |
External links | Elife / PubMed:33063666 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.92 - 3.35 Å |
Structure data | EMDB-21511, PDB-6w1j: EMDB-21512, PDB-6w1m: EMDB-21518, PDB-6w1y: |
Chemicals | ChemComp-S7Y: ChemComp-CL: ChemComp-S87: ChemComp-O7B: |
Source |
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Keywords | TRANSPORT PROTEIN |