Allosteric communication pipelines in G-protein-coupled receptors

Vaidehi, Nagarajan; Bhattacharya, Supriyo

doi:10.1016/j.coph.2016.07.010

Cited by 36 publications

(41 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Data histograms were plotted using Matplotlib software 63 . Allosteric communication analysis was performed with Allosteer 64 , 65 , an in-house developed software package, which calculates mutual information in the dihedral angle movements between amino-acid pairs across the dimer. Briefly, we first calculated mutual information in dihedral angle movement 64 , 66 , between the set of residues near the L115 and the set of residues in the vicinity of residues K160 and R178.…”

Section: Methodsmentioning

confidence: 99%

C-NHEJ without indels is robust and requires synergistic function of distinct XLF domains

et al. 2018

Self Cite

View full text Add to dashboard Cite

To investigate the fidelity of canonical non-homologous end joining (C-NHEJ), we developed an assay to detect EJ between distal ends of two Cas9-induced chromosomal breaks that are joined without causing insertion/deletion mutations (indels). Here we find that such EJ requires several core C-NHEJ factors, including XLF. Using variants of this assay, we find that C-NHEJ is required for EJ events that use 1–2, but not ≥3, nucleotides of terminal microhomology. We also investigated XLF residues required for EJ without indels, finding that one of two binding domains is essential (L115 or C-terminal lysines that bind XRCC4 and KU/DNA, respectively), and that disruption of one of these domains sensitizes XLF to mutations that affect its dimer interface, which we examined with molecular dynamic simulations. Thus, C-NHEJ, including synergistic function of distinct XLF domains, is required for EJ of chromosomal breaks without indels.

show abstract

Section: Methodsmentioning

confidence: 99%

C-NHEJ without indels is robust and requires synergistic function of distinct XLF domains

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…The MD simulation trajectories were used to calculate the allosteric communication pipelines for each agonist-GPCR pair using the Allosteer computational method (Bhattacharya and Vaidehi, 2014a,b;Bhattacharya et al, 2016;Vaidehi and Bhattacharya, 2016), which we have developed previously elsewhere. The details of the Allosteer computational method for calculating the allosteric communication pipelines in GPCRs are described by Bhattacharya and Vaidehi (2014a,b).…”

Section: Allosteric Pipeline Analysismentioning

confidence: 99%

“…For each MD run, the top 10% of allosteric pathways ranked by the total mutual information were used for further calculation of the ligand bias. The strength of an allosteric communication pipeline is the number of overlapping allosteric communication pathways contained in the pipeline (Bhattacharya and Vaidehi, 2014a;Vaidehi and Bhattacharya, 2016).…”

Section: Allosteric Pipeline Analysismentioning

confidence: 99%

Identifying Functional Hotspot Residues for Biased Ligand Design in G-Protein-Coupled Receptors

Nivedha

Tautermann

Bhattacharya

et al. 2018

Molecular Pharmacology

Self Cite

View full text Add to dashboard Cite

G-protein-coupled receptors (GPCRs) mediate multiple signaling pathways in the cell, depending on the agonist that activates the receptor and multiple cellular factors. Agonists that show higher potency to specific signaling pathways over others are known as "biased agonists" and have been shown to have better therapeutic index. Although biased agonists are desirable, their design poses several challenges to date. The number of assays to identify biased agonists seems expensive and tedious. Therefore, computational methods that can reliably calculate the possible bias of various ligands ahead of experiments and provide guidance, will be both cost and time effective. In this work, using the mechanism of allosteric communication from the extracellular region to the intracellular transducer protein coupling region in GPCRs, we have developed a computational method to calculate ligand bias ahead of experiments. We have validated the method for several -arrestin-biased agonists in-adrenergic receptor (2AR), serotonin receptors 5-HT1B and 5-HT2B and for G-protein-biased agonists in the -opioid receptor. Using this computational method, we also performed a blind prediction followed by experimental testing and showed that the agonist carmoterol is-arrestin-biased in 2AR. Additionally, we have identified amino acid residues in the biased agonist binding site in both2AR and -opioid receptors that are involved in potentiating the ligand bias. We call these residues functional hotspots, and they can be used to derive pharmacophores to design biased agonists in GPCRs.

show abstract

“…Obviously, individual class A receptor naturally has its intrinsic activation mechanism(s), as a result of the diversified sequences, ligands and physiological functions. Indeed, receptor-specific activation pathways (including mechanisms of orthosteric, positive or negative allosteric modulators, biased signalling/selectivity of downstream effectors) 5, 9, 17, 43–48 have been revealed by both experimental studies including biophysical (such as X-ray, cryo-EM, NMR, FRET/BRET, DEER) 2, 9, 14, 27, 33, 43, 49–52 , biochemical 28, 39 and computational approaches (such as evolutionary trace analysis 26, 30 and molecular dynamics simulations 16, 25, 31, 53 ), especially for the prototypical receptors such as rhodopsin, β 2 -adrenergic and A 2A receptors. These studies demonstrated the complexity and plasticity of signal transduction of GPCRs.…”

Section: Discussionmentioning

confidence: 99%

Universal activation mechanism of class A GPCRs

Zhou

Yang

et al. 2019

Preprint

View full text Add to dashboard Cite

19Class A G protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. 20 GPCR activation is an allosteric process that links agonist binding to G protein recruitment, with the 21 hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 22 movement and the key residue-level changes of this trigger remain less well understood. Here, by 23 analyzing over 230 high-resolution structures of class A GPCRs, we discovered a modular, universal 24 GPCR activation pathway that unites previous findings into a common activation mechanism, directly 25 linking the bottom of ligand-binding pocket with G protein-coupling region. We suggest that the 26 modular nature of the universal GPCR activation pathway allowed for the decoupling of the evolution 27 of the ligand binding site, G protein binding region and the residues important for receptor activation. 28 Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins 29 for signal transduction in nature. 30

show abstract

Allosteric communication pipelines in G-protein-coupled receptors

Cited by 36 publications

References 52 publications

C-NHEJ without indels is robust and requires synergistic function of distinct XLF domains

C-NHEJ without indels is robust and requires synergistic function of distinct XLF domains

Identifying Functional Hotspot Residues for Biased Ligand Design in G-Protein-Coupled Receptors

Universal activation mechanism of class A GPCRs

Contact Info

Product

Resources

About