Molecular insights into GPCR structure, a vital drug target

Ligand efficacy in GPCR signaling: Molecular insights.


In a collaboration, St. Jude scientists studied the adrenaline receptor at an atomic level. They identified amino acids controlling critical properties of the ligand. This receptor, part of the GPCR family, is crucial for many FDA-approved drugs. 

Understanding how GPCRs respond to natural or therapeutic ligands is vital for precise therapies. The study, published in Science, used a detailed approach, replacing one amino acid at a time in the β2-adrenergic receptor to understand each one’s role in mediating signaling responses. This research could pave the way for developing new therapies with specific effects on receptor activity.

Co-corresponding author M. Madan Babu, Ph.D., from St. Jude’s Department of Structural Biology, Center of Excellence for Data-Driven Discovery director and the George J. Pedersen Endowed Chair in Biological Data Science said, “Scientists learn how genes contribute to cell function by disrupting them one at a time. We asked, ‘Why don’t we take this one level deeper? Let’s understand how every amino acid contributes to the functioning of a receptor by mutating them, one amino acid at a time. Through evolution, every amino acid in the receptor has been sculpted somehow to ensure that it binds the natural ligand, in this case adrenaline, and elicits the appropriate physiological response.” 

GPCRs are cell membrane proteins that transmit signals from outside to inside. In β2AR, adrenaline binds out, causing shape changes. These changes activate G proteins, triggering responses inside the cell. Adrenaline, acting on GPCRs like β2AR, can induce the fight-or-flight response across various tissues.

To understand amino acids in GPCR, Dr. Heydenreich mutated each of the 412 in β2AR. Testing each mutant’s response to adrenaline, she assessed efficacy and potency, measuring the maximum response and ligand amount needed for half the answer. 

Surprisingly, only 80 amino acids affected these properties, with one-third located where ligand or G protein binds. Some amino acids control efficacy, some potency, and others both. This insight can guide the design of more potent and efficacious drugs by influencing specific residues in new ligands, providing opportunities for fine-tuning drug responses.

“We’ve measured efficacy and potency for years. However, now we understand how specific amino acids in a protein influence these properties,” explained Dr. Babu. The results show that distinct mechanisms can independently regulate potency and efficacy. This insight forms a basis for understanding how genetic variation affects drug responses in individuals, as Dr. Bouvier from the University of Montreal noted.

Previous research showed the structure of active and inactive states of β2AR. Building on this, researchers investigated the role of amino acids not involved in binding. They systematically examined residues unique to the active state to understand their importance. Using a data science framework, they integrated pharmacological and structural data, revealing a comprehensive picture of GPCR signaling. 

This provided insights into the allosteric network governing efficacy and potency. The study aims to explore transient sub-states and the conformational landscape of proteins, delving even deeper into understanding GPCR signaling at the atomic level.

“We now target mutants affecting efficacy, potency, or both,” said Heydenreich. Molecular dynamics and experiments will uncover mechanisms influencing signaling response in the mutants. 

Babu explains they’re exploring this through a St. Jude Research Collaborative on GPCRs. Beyond “driver” residues mediating active state contacts, they’ll study “passenger” amino acids and “modulator” residues, expanding insights. Their data science approach, not limited to β2AR, can extend to any GPCR, enhancing our understanding of these vital drug targets’ mechanics.

In conclusion, this research sheds light on the molecular intricacies of GPCR structure. It provides insights that can revolutionize the development of new and more effective therapeutic drugs.

Journal reference:

  1. FRANZISKA M. HEYDENREICH ,MARIA MARTI-SOLANO et al., Molecular determinants of ligand efficacy and potency in GPCR signaling. Science. DOI:10.1126/science.adh1859


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