Multi-state Modeling of G-protein Coupled Receptors at Experimental Accuracy

Ligand Docking ◽

Gpcr Activation ◽

The Family ◽

Activation Mechanisms ◽

The family of G-protein coupled receptors (GPCRs) is one of the largest protein families in the human genome. GPCRs transduct chemical signals from extracellular to intracellular regions via a conformational switch between active and inactive states upon ligand binding. While experimental structures of GPCRs remain limited, high-accuracy computational predictions are now possible with AlphaFold2. However, AlphaFold2 only predicts one state and is biased towards the inactive conformation. Here, a multi-state prediction protocol is introduced that extends AlphaFold2 to predict either active or inactive states at very high accuracy using state-annotated templated GPCR databases. The predicted models accurately capture the main structural changes upon activation of the GPCR at the atomic level. The models were also highly successful in predicting ligand binding poses via protein-ligand docking. We expect that high accuracy GPCR models in both activation states will promote understanding in GPCR activation mechanisms and drug discovery for GPCRs. At the time, the new protocol paves the way towards capturing the dynamics of proteins at high-accuracy via machine-learning methods.

Ligand Docking Methods to Recognize Allosteric Inhibitors for G-protein Coupled Receptors

10.20944/preprints202012.0085.v1 ◽

2020 ◽

Author(s):

K Harini ◽

S Jayashree ◽

Vikas Tiwari ◽

Sneha Vishwanath ◽

Ramanathan Sowdhamini

Keyword(s):

Binding Site ◽

G Protein ◽

Drug Targets ◽

Ligand Docking ◽

Computational Docking ◽

Cellular Processes ◽

Activation Mechanisms ◽

Approved Drugs ◽

G-protein coupled receptors (GPCRs) are large protein families known to be important in many cellular processes. They are well known for their allosteric activation mechanisms. They are drug targets for several FDA-approved drugs. We have investigated the diversity of the ligand binding site for these class of proteins against their cognate ligands using computational docking, even if their structures are known in the ligand-complexed form. The cognate ligand of some of these receptors dock at allosteric binding site, with better score than the binding at the conservative site. Further, ligands obtained from GLASS database, which consists of experimentally verified GPCR ligands, also show allosteric binding to GPCRs. The allosteric binders show strong affinity to the binding site, though the residues at the binding site are not conserved across GPCR subfamilies.

Adhesion GPCRs in Glioblastoma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab046 ◽

2021 ◽

Author(s):

Gabriele Stephan ◽

Niklas Ravn-Boess ◽

Dimitris G Placantonakis

Keyword(s):

G Protein ◽

The Past ◽

Novel Treatment ◽

The Family ◽

Health And Disease ◽

Basic Biology ◽

G Protein Coupled ◽

Potential Use ◽

Receptor Family

Abstract Members of the adhesion family of G protein-coupled receptors (GPCRs) have received attention for their roles in health and disease, including cancer. Over the past decade, several members of the family have been implicated in the pathogenesis of glioblastoma. Here, we discuss the basic biology of adhesion GPCRs and review in detail specific members of the receptor family with known functions in glioblastoma. Finally, we discuss the potential use of adhesion GPCRs as novel treatment targets in neuro-oncology.

Ion channels and G protein-coupled receptors as targets for invertebrate pest control: from past challenges to practical insecticides

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbab089 ◽

2021 ◽

Author(s):

Yoshihisa Ozoe

Keyword(s):

Ion Channels ◽

G Protein ◽

Pest Control ◽

Gaba Receptors ◽

Chloride Channels ◽

Structural Changes ◽

Octopamine Receptors ◽

Sites Of Action ◽

Abstract In the late 1970s, we discovered that toxic bicyclic phosphates inhibit the generation of miniature inhibitory junction potentials, implying their antagonism of γ-aminobutyric acid (GABA) receptors (GABARs; GABA-gated chloride channels). This unique mode of action provided a strong incentive for our research on GABARs in later years. Furthermore, minor structural changes conferred insect GABAR selectivity to this class of compounds, convincing us of the possibility of GABARs as targets for insecticides. Forty years later, third-generation insecticides acting as allosteric modulator antagonists at a distinctive site of action in insect GABARs were developed. G protein-coupled receptors (GPCRs) are also promising targets for pest control. We characterized phenolamine receptors functionally and pharmacologically. Of the tested receptors, β-adrenergic-like octopamine receptors were revealed to be the most sensitive to the acaricide/insecticide amitraz. Given the presence of multiple sites of action, ion channels and GPCRs remain potential targets for invertebrate pest control.

Applications of molecular replacement to G protein-coupled receptors

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s090744491301322x ◽

2013 ◽

Vol 69 (11) ◽

pp. 2287-2292 ◽

Cited By ~ 3

Author(s):

Andrew C. Kruse ◽

Aashish Manglik ◽

Brian K. Kobilka ◽

William I. Weis

Keyword(s):

G Protein ◽

Structural Biology ◽

Structural Information ◽

Integral Membrane Proteins ◽

Molecular Replacement ◽

Gpcr Activation ◽

Health And Disease ◽

Almost All ◽

G protein-coupled receptors (GPCRs) are a large class of integral membrane proteins involved in regulating virtually every aspect of human physiology. Despite their profound importance in human health and disease, structural information regarding GPCRs has been extremely limited until recently. With the advent of a variety of new biochemical and crystallographic techniques, the structural biology of GPCRs has advanced rapidly, offering key molecular insights into GPCR activation and signal transduction. To date, almost all GPCR structures have been solved using molecular-replacement techniques. Here, the unique aspects of molecular replacement as applied to individual GPCRs and to signaling complexes of these important proteins are discussed.

GPCR activation mechanisms across classes and macro/microscales

10.21203/rs.3.rs-354879/v1 ◽

2021 ◽

Author(s):

David Gloriam ◽

Alexander Hauser ◽

Albert Kooistra ◽

Christian Munk ◽

M. Madan Babu

Keyword(s):

Residue Level ◽

Conformational Selection ◽

Class A ◽

New Methods ◽

Allosteric Communication ◽

Gpcr Activation ◽

Activation Mechanisms ◽

Clinical Drugs ◽

Abstract Two-thirds of human hormones and one-third of clinical drugs activate ~350 G protein-coupled receptors belonging to four classes: A, B1, C and F. Whereas a model of activation has been described for class A, very little is known about the activation of the other classes which differ by being activated by endogenous ligands bound mainly or entirely extracellularly. Here, we show that although they use the same structural scaffold and share several helix macroswitches, the GPCR classes differ in their microswitch residue positions and contacts. We present molecular mechanistic maps of activation for each GPCR class and new methods for contact analysis applicable for any functional determinants. This is the first superfamily residue-level rationale for conformational selection and allosteric communication by ligands and G proteins laying the foundation for receptor-function studies and drugs with the desired modality.