Loss of a water-mediated network results in reduced agonist affinity in a β2-adrenergic receptor clinical variant
| Autor: | Durba Sengupta, Manali Joshi, Aditi Tandale, Krushna Sonar, Siddhanta V. Nikte |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Agonist 010304 chemical physics medicine.drug_class Chemistry Allosteric regulation Biophysics 01 natural sciences Biochemistry Analytical Chemistry β2 adrenergic receptor Cell biology 03 medical and health sciences Transmembrane domain 030104 developmental biology Interaction network 0103 physical sciences medicine Binding site Receptor Molecular Biology G protein-coupled receptor |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1869:140605 |
| ISSN: | 1570-9639 |
| Popis: | The β2-adrenergic receptor (β2AR) is a member of the G protein-coupled receptor (GPCR) family that is an important drug target for asthma and COPD. Clinical studies coupled with biochemical data have identified a critical receptor variant, Thr164Ile, to have a reduced response to agonist-based therapy, although the molecular mechanism underlying this seemingly "non-deleterious" substitution is not clear. Here, we couple molecular dynamics simulations with network analysis and free-energy calculations to identify the molecular determinants underlying the differential drug response. We are able to identify hydration sites in the transmembrane domain that are essential to maintain the integrity of the binding site but are absent in the variant. The loss of these hydration sites in the variant correlates with perturbations in the intra-protein interaction network and rearrangements in the orthosteric ligand binding site. In conjunction, we observe an altered binding and reduced free energy of a series of agonists, in line with experimental trends. Our work identifies a functional allosteric pathway connected by specific hydration sites in β2AR that has not been reported before and provides insight into water-mediated networks in GPCRs in general. Overall, the work is one of the first step towards developing variant-specific potent and selective agonists. |
| Databáze: | OpenAIRE |
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