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G Protein-coupled Receptors

G Protein-coupled Receptors

G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...

Transducer Mechanism: G Protein–Coupled Receptors

Transducer Mechanism: G Protein–Coupled Receptors

G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...

Activation and Inactivation of G Proteins

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...

Conserved Binding Sites

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...

G-protein Coupled Receptors

G-protein Coupled Receptors

G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.

The Two-State Receptor Model

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
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Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET

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Identifying multiple active conformations in the G protein-coupled receptor activation landscape using computational

Sijia S Dong¹, William A Goddard¹, Ravinder Abrol²

¹Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA, United States.

Methods in Cell Biology

|October 2, 2017

Summary

We developed ActiveGEnSeMBLE, a computational method to predict multiple G protein-coupled receptor (GPCR) conformations. This approach aids in understanding GPCR activation and designing targeted therapeutics.

Keywords:

Active GPCR conformations Conformational sampling G protein-coupled receptor G proteins GPCR activation Molecular dynamics Protein conformations Protein dynamics Protein structure prediction

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Area of Science:

Structural Biology
Computational Chemistry
Pharmacology

Background:

G protein-coupled receptors (GPCRs) are crucial membrane proteins for cellular signaling and therapeutic targets.
GPCR function relies on dynamic conformational changes, particularly during activation.
Experimental structure determination of GPCRs, especially high-energy active states, is challenging.

Purpose of the Study:

To develop a computational method for predicting multiple GPCR conformations, including active states.
To enable rational drug design by providing atomistic structures along GPCR activation pathways.
To overcome limitations of existing computational methods biased towards low-energy structures.

Main Methods:

Developed the ActiveGEnSeMBLE method for efficient prediction of GPCR conformational ensembles.
Employed systematic coarse grid sampling of helix tilts/rotations to explore GPCR transmembrane domain conformations.
Utilized TM3-TM6 intracellular distance as a surrogate for GPCR activation and identified energy wells for local sampling and molecular dynamics (MD) refinement.

Main Results:

ActiveGEnSeMBLE systematically predicts multiple active and inactive GPCR conformations.
The method identifies potential active-state energy wells within a vast conformational space.
It provides computationally affordable access to multiple candidate active-state conformations.

Conclusions:

ActiveGEnSeMBLE is a novel computational tool for predicting diverse GPCR conformations.
This method facilitates the study of GPCR activation landscapes and drug discovery.
It offers a computationally efficient approach to modeling high-energy, functionally relevant GPCR states.