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dc.contributor.authorMiao, Yinglong
dc.contributor.authorBhattarai, Apurba
dc.contributor.authorNguyen, Anh T. N.
dc.contributor.authorChristopoulos, Arthur
dc.contributor.authorMay, Lauren T.
dc.identifier.citationMiao, Y., Bhattarai, A., Nguyen, A., Christopoulos, A., & May, L. T. (2018). Structural Basis for Binding of Allosteric Drug Leads in the Adenosine A1 Receptor. Scientific reports, 8(1), 16836.
dc.descriptionThis work is licensed under a Creative Commons Attribution 4.0 International License.en_US
dc.description.abstractDespite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A1 receptor (A1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 Å away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A1AR, which will greatly facilitate the receptor structure-based drug design.en_US
dc.description.sponsorshipExtreme Science and Engineering Discovery Environment award TG-MCB170129en_US
dc.description.sponsorshipNational Energy Research Scientific Computing Center project M2874en_US
dc.description.sponsorshipAmerican Heart Association (Award 17SDG33370094)en_US
dc.description.sponsorshipCollege of Liberal Arts and Sciences at the University of Kansasen_US
dc.description.sponsorshipNHMRC Senior Principal Research Fellowen_US
dc.description.sponsorshipAustralian Heart Foundation Future Leader Fellowen_US
dc.publisherNature Researchen_US
dc.rights© The Author(s) 2018en_US
dc.titleStructural Basis for Binding of Allosteric Drug Leads in the Adenosine A1 Receptoren_US
kusw.kuauthorMiao, Yinglong
kusw.kuauthorBhattarai, Apurba
kusw.kudepartmentMolecular Biosciencesen_US
kusw.kudepartmentCenter for Computational Biologyen_US
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

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