Unveiling α1-AR secrets: breakthrough structures and targeted drug design

In a recent study published in Nature Communications, researchers explored the structural basis of agonist specificity of α1A-adrenergic receptors (α1-ARs).

Advancing the knowledge of the molecular basis of these interactions could enable the rational design of AR subtype-specific agonists and tap their full therapeutic potential in treating cardiovascular, neuropsychiatric, and inflammatory disorders.

Study: Structural basis of agonist specificity of α1A-adrenergic receptor. Image Credit: Gorodenkoff/Shutterstock.comStudy: Structural basis of agonist specificity of α1A-adrenergic receptor. Image Credit: Gorodenkoff/Shutterstock.com


ARs have three major subfamilies, viz., α1, α2, and β-type with three members each,- α1A, α1B, α1D, α2A, α2B, α2C, and β1, β2, and β3. They all mediate the workings of neurotransmitters secreted by the adrenal medulla, namely epinephrine and norepinephrine.

Researchers have not yet discovered selective pharmacological agonists for α1-ARs; hence, their therapeutic potential remains largely unexplored.

Preclinical genetic studies in mice have demonstrated the role of all α1-AR subtypes in several physiological functions, e.g., neurotransmission, metabolism, regulation of blood pressure, and cardiac hypertrophy. For instance, the α1A-AR is a vasopressor needed to maintain normal blood pressure in arteries.

To perform their function, α1-ARs bind to the Gq family of G-proteins. This coupling stimulated the cleaving of phosphatidylinositol-4,5-bisphosphate into inositol-1,4,5-trisphosphate by the enzymatic action of phospholipase C-β that leads to the release of intracellular calcium ions (Ca2+).

Studies have identified two structurally resembling α1A agonists, namely A61603, a selective α1A-AR agonist with high affinity, i.e., inactive against α1B-AR and α1D-AR. Another is epinephrine, an endogenous agonist for all ARs.

About the study

The present study used cryo-electron microscopy (cryo-EM) to decipher the molecular structures of α1A-AR/Gq complexes with epinephrine at 2.6 angstroms (Å) and A61603 at 3.0 Å.

They used epinephrine–α1A-AR–Gq and A61603–α1A-AR–Gq cryo-EM structures to set up the gaussian accelerated molecular dynamics (GaMD) simulation systems to explore the stability of these complexes.

The GaMD simulations and functional studies helped them examine the mechanisms of specificity of these interactions and validate key sites of A61603 mediating activation of α1A-AR.

Guided by the cryo-EM structures and GaMD simulations, the team also attempted to engineer α1A-AR variants that would lose the response to A61603, presuming this loss-of-function study would evidence the molecular basis of A61603-binding specificity. They also engineered α1B-AR mutants that could potently activate A61603.

The team created three point mutants, α1A-AR, α1A-AR, and α1A-AR, by mutating three residues involved in hydrophobic interactions with A61603, namely V1855.40, A1895.44, and M2926.55 to the corresponding residues in α1B-AR.

Since α1A-AR was coupled to Gq to form a signaling complex, they used Ca2+ responses as a functional readout. 

Results and conclusion

Cryo-EM uncovered the molecular basis for the binding specificity of A61603 for α1A-AR and the different conformations of epinephrine in interacting with α-ARs versus β-ARs.

While the structures of the α1A-AR–Gq complex with A61603 or epinephrine were similar, they exhibited local conformational variations, especially in the orthosteric ligand-binding pockets extending to the G-protein-interacting site.

Comparing the active state structures of α1A-AR with the inactive state structure of α1B-AR bound with cyclazosin, an inverse agonist, revealed peculiar conformational changes related to class A G protein-coupled receptors (GPCR) activation.

The root-mean-square deviation between the cryo-EM structures of the active α1A-AR vs. inactive α1B-AR was 1.6 Å. 

The protonated amine of epinephrine formed a salt bridge with residue D1063 of the α1A-AR–Gq complex, an interaction considered critical for both affinity and efficacy.

Furthermore, it adopted binding conformations with <2 Å root-mean-square derivation (RMSD). Interestingly, this ligand maintained stable salt bridge interactions with α1A-AR residues D1063 and S1885 at 3.82 and 3.10 (±0.33) Å, respectively.

Regarding ligand-binding pocket residues, α1A-AR and α1B-AR had nearly identical composition except three residues: V1855.40 in α1A-AR but A2045.40 in α1B-AR, A1895.44 in α1A-AR and S2085.44 in α1B-AR, and M2926.55 in α1A-AR but L3146.55 in α1B-AR.

Hydrophobic M2926.55 and V1855.40 of α1A-AR defined the specificity of A61603 for α1A-AR. Thus, the researchers recommended further investigating this hydrophobic pocket when designing AR subtype-specific ligands.

GaMD simulations data unveiled the molecular interactions between A61603 and α1A-AR. The conformation of A61603 was comparable to that in the cryo-EM structure. α1A-AR residue S1885 formed hydrogen bonds with N, O, and O2 atoms of the methanesulfonamide group of A61603.

The triple mutant α1A-AR(V185A, A189S, M292L) decreased the affinity of the A61603 response by >1,000-fold; yet, it was functional in response to epinephrine.

The wild-type α1A-AR (control) yielded robust but dose-dependent Ca2+ responses to A61603 with a 50% of the maximal response (EC50) of ~1 nM, albeit with a similar amplitude at saturating doses than saturating epinephrine.

Together, the study data provided much-needed insights to facilitate the development of selective agonists for all three α1-AR subtypes and pharmacological agonists customized for other related receptors.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.


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