p<i>K</i><sub>a</sub> Calculations of GPCRs: Understanding Protonation States in Receptor Activation
The increase in the available G protein-coupled receptor (GPCR) structures has been pivotal in helping to understand their activation process. However, the role of protonation-conformation coupling in GPCR activation still needs to be clarified. We studied the protonation behavior of the highly conserved Asp<sup>2.50</sup> residue in five different class A GPCRs (active and inactive conformations) using a linear response approximation (LRA) p<i>K</i><sub>a</sub> calculation protocol. We observed consistent differences (1.3 p<i>K</i> units) for the macroscopic p<i>K</i><sub>a</sub> values between the inactive and active states of the A2AR and B2AR receptors, indicating the protonation of Asp<sup>2.50</sup> during GPCR activation. This process seems to be specific and not conserved, as no differences were observed in the p<i>K</i><sub>a</sub> values of the remaining receptors (CB1R, NT1R, and GHSR).
Authors
- Carlos A.V. Barreto (ORCID: https://orcid.org/0000-0003-1459-7680)
- João N. M. Vitorino (ORCID: https://orcid.org/0000-0003-3158-1680)
- Pedro B. P. S. Reis (ORCID: https://orcid.org/0000-0003-3563-6239)
- Irina S. Moreira (ORCID: https://orcid.org/0000-0003-2970-5250)
- Miguel Machuqueiro (ORCID: https://orcid.org/0000-0001-6923-8744)
Institutions
- University of Lisbon (PT)
- University of Coimbra (PT)
Publication Details
- Journal
- Journal of Chemical Information and Modeling
- Published
- 2024-08-16
- DOI
- https://doi.org/10.1021/acs.jcim.4c01125
- Citations
- 6
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Universidade de Coimbra
- Fundação para a Ciência e a Tecnologia
- European Regional Development Fund