Bihelix: Towards <i>de novo</i> structure prediction of an ensemble of G‐protein coupled receptor conformations

Abrol, Ravinder; Bray, Jenelle K.; Goddard, William A.

doi:10.1002/prot.23216

Cited by 43 publications

(82 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The SuperBiHelix procedure starts with a GPCR bundle template, obtained either from X-ray experiments or from previously predicted and validated GPCR structures. This template is defined by the 6 × 7 = 42 degrees of freedom: x, y, h, θ, ϕ, and η values for each of the seven TM helices, as described earlier (17). Because some helices may have kinks and bends, the helical axis is defined as its least moment of inertia.…”

Section: Methodsmentioning

confidence: 99%

“…These BiHelix energies are partitioned into intrahelical and interhelical components to avoid multiple counting of the intrahelical contributions, and the energy of the entire complex is then calculated, as described in SI Text (17). Although the calculation of the energy of a complex based on its BiHelix energies is very fast, the calculation of all possible configurations is still computationally expensive.…”

Section: Methodsmentioning

confidence: 99%

“…The SuperBiHelix method builds upon the BiHelix method (17). We showed earlier that, starting with the known X-ray structure, the BiHelix method identifies correctly the optimum packing from the (12) 7 = 35 million conformations differing by independent 30°rotations about the axes of the seven transmembrane helices.…”

Section: Significancementioning

confidence: 99%

See 2 more Smart Citations

SuperBiHelix method for predicting the pleiotropic ensemble of G-protein–coupled receptor conformations

Bray

Abrol

Goddard

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

There is overwhelming evidence that G-protein-coupled receptors (GPCRs) exhibit several distinct low-energy conformations, each of which might favor binding to different ligands and/or lead to different downstream functions. Understanding the function of such proteins requires knowledge of the ensemble of low-energy configurations that might play a role in this pleiotropic functionality. We earlier reported the BiHelix method for efficiently sampling the (12) 7 = 35 million conformations resulting from 30°rotations about the axis (η) of all seven transmembrane helices (TMHs), showing that the experimental structure is reliably selected as the best conformation from this ensemble. However, various GPCRs differ sufficiently in the tilts of the TMHs that this method need not predict the optimum conformation starting from any other template. In this paper, we introduce the SuperBiHelix method in which the tilt angles (θ, φ) are optimized simultaneously with rotations (η) efficiently enough that it is practical and sufficient to sample (5 × 3 × 5) 7 = 13 trillion configurations. This method can correctly identify the optimum structure of a GPCR starting with the template from a different GPCR. We have validated this method by predicting known crystal structure conformations starting from the template of a different protein structure. We find that the SuperBiHelix conformational ensemble includes the higher energy conformations associated with the active protein in addition to those associated with the more stable inactive protein. This methodology was then applied to design and experimentally confirm structures of three mutants of the CB1 cannabinoid receptor associated with different functions.protein structure prediction | A 2A adenosine receptor | β 2 -adrenergic receptor | constitutive activity | functional selectivity

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

SuperBiHelix method for predicting the pleiotropic ensemble of G-protein–coupled receptor conformations

Bray

Abrol

Goddard

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…structure for the sweet receptor, we used our GEnSeMBLE Complete Sampling Hierarchical Scoring (CoS-HS) technique (12). This has been successful at predicting the 3D structures of other GPCRs [such as chemokine CCR5 (13) …”

Section: Significancementioning

confidence: 99%

Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists

Kim

Chen

Abrol

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The sweet taste in humans is mediated by the TAS1R2/TAS1R3 G protein-coupled receptor (GPCR), which belongs to the class C family that also includes the metabotropic glutamate and γ-aminobutyric acid receptors. We report here the predicted 3D structure of the fulllength TAS1R2/TAS1R3 heterodimer, including the Venus Flytrap Domains (VFDs) [in the closed-open (co) active conformation], the cysteine-rich domains (CRDs), and the transmembrane domains (TMDs) at the TM56/TM56 interface. We observe that binding of agonists to VFD2 of TAS1R2 leads to major conformational changes to form a TM6/TM6 interface between TMDs of TAS1R2 and TAS1R3, which is consistent with the activation process observed biophysically on the metabotropic glutamate receptor 2 homodimer. We find that the initial effect of the agonist is to pull the bottom part of VFD3/TAS1R3 toward the bottom part of VFD2/ TAS1R2 by ∼6 Å and that these changes get transmitted from VFD2 of TAS1R2 (where agonists bind) through the VFD3 and the CRD3 to the TMD3 of TAS1R3 (which couples to the G protein). These structural transformations provide a detailed atomistic mechanism for the activation process in GPCR, providing insights and structural details that can now be validated through mutation experiments.GPCR activation | class C GPCR | molecular dynamics | noncaloric sweetener G protein-coupled receptors (GPCRs) play an essential signaling function throughout all eukaryote systems, serving as the basis for detecting light, smell, nociceptive signaling, and taste along with dopamine, serotonin, adrenaline, etc. (1). Generally, binding of a signaling ligand to the exterior of a cell causes a G protein at the intracellular interface to dissociate, which then triggers a sequence of events that respond to the signal. There are now structures for ∼32 human GPCRs, including 4 that have been activated (2); however, a detailed understanding of the activation mechanisms of monomeric GPCRs is still lacking (3). This is most unfortunate because about half the drugs under development involve GPCRs and it is most important to know whether the drug will serve as an agonist to activate the G protein or as an antagonist or inverse agonist.Particularly interesting here are the class C GPCRs, which in addition to a seven-helix transmembrane domain (TMD) include a large N-terminal segment consisting of a Venus Flytrap Domain (VFD) and a cysteine-rich domain (CRD). Biophysical measurements on the class C glutamate dimer receptor 2 (mGluR2) have shown that the inactive or resting state (R) dimer interface involves contacts between TMs 4 and 5 of each TMD, whereas formation of the fully active state is associated with motions in which the extracellular (EC) projections of the two TM6s move together to form a TM6-TM6 interface (4).In addition, biophysical experiments on the class C sweet receptor, consisting of the TAS1R2/TAS1R3 heterodimer, indicate that sucrose and glucose bind to the VFD of both the TAS1R2 and TAS1R3 subunits (5, 6), whereas other sweeteners, such as aspartame and st...

show abstract

“…Kim et al published the development of H1, H2, H3 and H4 receptor models using the GEnSeMBLE (GPCR ensemble of structures in membrane bilayer environment) Monte Carlo protocol [37] focusing on the binding mode analysis of subtype selective H3 antagonists [38]. During model building ~35 million combinations of helix packings were sampled to predict the 10 most stable packings for each of the four subtypes.…”

Section: H3 Receptormentioning

confidence: 99%

Structure-based discovery and binding site analysis of histamine receptor ligands

Kingsford-Adaboh

Keserü

2016

Expert Opinion on Drug Discovery

View full text Add to dashboard Cite

Introduction: Application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors. Areas covered: In this paper, we review the development of histamine receptors models and their application on drug discovery. Expert opinion: In our opinion, the application of atomistic histamine receptor models played a significant role in understanding key ligand-receptor interactions as well as in the discovery of novel chemical starting points. The recently solved H1 receptor structure is a major milestone in structure-based drug discovery, however our analysis also demonstrate that for building H3 and H4 receptor homology models other GPCRs may be more suitable as a template. For these receptors we envisage that the development of higher quality homology models will significantly contribute to the discovery and optimization of novel H3 and H4 ligands.

show abstract

Bihelix: Towards de novo structure prediction of an ensemble of G‐protein coupled receptor conformations

Cited by 43 publications

References 55 publications

SuperBiHelix method for predicting the pleiotropic ensemble of G-protein–coupled receptor conformations

SuperBiHelix method for predicting the pleiotropic ensemble of G-protein–coupled receptor conformations

Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists

Structure-based discovery and binding site analysis of histamine receptor ligands

Contact Info

Product

Resources

About