WFRF:(Fleetwood Oliver 1990 )
Sökning: WFRF:(Fleetwood Oliver 1990 ) > Allosteric Effect o...
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| Fältnamn | Indikatorer | Metadata |
|---|---|---|
| 000 | 03933naa a2200349 4500 | |
| 001 | oai:DiVA.org:kth-309546 | |
| 003 | SwePub | |
| 008 | 220314s2021 | |||||||||||000 ||eng| | |
| 024 | 7 | a https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-3095462 URI |
| 024 | 7 | a https://doi.org/10.1021/acs.jcim.1c008262 DOI |
| 040 | a (SwePub)kth | |
| 041 | a engb eng | |
| 042 | 9 SwePub | |
| 072 | 7 | a ref2 swepub-contenttype |
| 072 | 7 | a art2 swepub-publicationtype |
| 100 | 1 | a Chen, Yueu KTH,Science for Life Laboratory, SciLifeLab,Tillämpad fysik4 aut0 (Swepub:kth)u1scuz81 |
| 245 | 1 0 | a Allosteric Effect of Nanobody Binding on Ligand-Specific Active States of the beta 2 Adrenergic Receptor |
| 264 | c 2021-11-15 | |
| 264 | 1 | b American Chemical Society (ACS),c 2021 |
| 338 | a print2 rdacarrier | |
| 500 | a QC 20220314 | |
| 520 | a Nanobody binding stabilizes G-protein-coupled receptors (GPCR) in a fully active state and modulates their affinity for bound ligands. However, the atomic-level basis for this allosteric regulation remains elusive. Here, we investigate the conformational changes induced by the binding of a nanobody (Nb80) on the active-like beta 2 adrenergic receptor (beta 2AR) via enhanced sampling molecular dynamics simulations. Dimensionality reduction analysis shows that Nb80 stabilizes structural features of the beta 2AR with an similar to 14 angstrom outward movement of transmembrane helix 6 and a close proximity of transmembrane (TM) helices 5 and 7, and favors the fully active-like conformation of the receptor, independent of ligand binding, in contrast to the conditions under which no intracellular binding partner is bound, in which case the receptor is only stabilized in an intermediateactive state. This activation is supported by the residues located at hotspots located on TMs 5, 6, and 7, as shown by supervised machine learning methods. Besides, ligand-specific subtle differences in the conformations assumed by intracellular loop 2 and extracellular loop 2 are captured from the trajectories of various ligand-bound receptors in the presence of Nb80. Dynamic network analysis further reveals that Nb80 binding triggers tighter and stronger local communication networks between the Nb80 and the ligand-binding sites, primarily involving residues around ICL2 and the intracellular end of TM3, TM5, TM6, as well as ECL2, ECL3, and the extracellular ends of TM6 and TM7. In particular, we identify unique allosteric signal transmission mechanisms between the Nb80-binding site and the extracellular domains in conformations modulated by a full agonist, BI167107, and a G-protein-biased partial agonist, salmeterol, involving mainly TM1 and TM2, and TM5, respectively. Altogether, our results provide insights into the effect of intracellular binding partners on the GPCR activation mechanism, which should be taken into account in structure-based drug discovery. | |
| 650 | 7 | a NATURVETENSKAPx Biologix Biokemi och molekylärbiologi0 (SwePub)106022 hsv//swe |
| 650 | 7 | a NATURAL SCIENCESx Biological Sciencesx Biochemistry and Molecular Biology0 (SwePub)106022 hsv//eng |
| 700 | 1 | a Fleetwood, Oliver,d 1990-u KTH,Biofysik,Science for Life Laboratory, SciLifeLab4 aut0 (Swepub:kth)u1x7tr10 |
| 700 | 1 | a Perez-Conesa, Sergiou KTH,Science for Life Laboratory, SciLifeLab4 aut0 (Swepub:kth)u1occu31 |
| 700 | 1 | a Delemotte, Lucieu KTH,Biofysik,Science for Life Laboratory, SciLifeLab,Dept Appl Phys, Sci Life Lab, SE-17121 Solna, Sweden.4 aut0 (Swepub:kth)u15w0he7 |
| 710 | 2 | a KTHb Science for Life Laboratory, SciLifeLab4 org |
| 773 | 0 | t Journal of Chemical Information and Modelingd : American Chemical Society (ACS)g 61:12, s. 6024-6037q 61:12<6024-6037x 1549-9596x 1549-960X |
| 856 | 4 | u https://doi.org/10.1021/acs.jcim.1c00826y Fulltext |
| 856 | 4 8 | u https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-309546 |
| 856 | 4 8 | u https://doi.org/10.1021/acs.jcim.1c00826 |
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