Dynamic allosteric networks drive adenosine A<sub>1</sub> receptor activation and G-protein coupling
- 주제(키워드) adenosine A1 receptor , activation pathway , energy networks , transient pockets , allosteric modulators , None
- 주제(기타) Biology
- 설명문(일반) [Maria-Solano, Miguel A.; Choi, Sun] Ewha Womans Univ, Coll Pharm, Global AI Drug Discovery Ctr, Seoul, South Korea; Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Green Submitted; Green Published; Gold Open Access
- 발행기관 eLIFE SCIENCES PUBL LTD
- 발행년도 2023
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000213481
- 본문언어 영어
- Published As https://doi.org/10.7554/eLife.90773
- PubMed 37656635
초록/요약
G-protein coupled receptors (GPCRs) present specific activation pathways and signaling among receptor subtypes. Hence, an extensive knowledge of the structural dynamics of the receptor is critical for the development of therapeutics. Here, we target the adenosine A(1) receptor (A(1)R), for which a negligible number of drugs have been approved. We combine molecular dynamics simulations, enhanced sampling techniques, network theory and pocket detection to decipher the activation pathway of A(1)R, decode the allosteric networks and identify transient pockets. The A(1)R activation pathway reveal hidden intermediate and pre-active states together with the inactive and fully-active states observed experimentally. The protein energy networks computed throughout these conformational states successfully unravel the extra and intracellular allosteric centers and the communication pathways that couples them. We observe that the allosteric networks are dynamic, being increased along activation and fine-tuned in presence of the trimeric G-proteins. Overlap of transient pockets and energy networks uncover how the allosteric coupling between pockets and distinct functional regions of the receptor is altered along activation. By an in-depth analysis of the bridge between activation pathway, energy networks and transient pockets, we provide a further understanding of A(1)R. This information can be useful to ease the design of allosteric modulators for A(1)R.
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