g protein coupled receptor(gpcr)

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G-Protein Coupled Receptor (GPCR)


OUTLINEIntroductionClassificationStructureActivation MechanismSignalingConclusion

INTRODUCTIONGPCR or G-protein coupled receptor/Seven transmembrane domain receptor/Heptahelical receptor.Largest known class of transmembrane proteins conserved throughout the evolution.~4% of human genome (~1265 in number) encodes for these receptors.Play a significant role in controlling the sense of smell, taste, vision, hearing and touch in humans.

GPCR Tree of Life

Mol Pharmacol, 2005GPCR is the largest known class of biologically important transmembrane proteins conserved throughout the evolution.

Later in 2003, GPCR classified in to Five families according to the GRAFS system : Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin) by Fredriksson.ClassificationAnnu Rev Pharmacol Toxicol, 2013

Difference Between SubfamiliesThe G proteincoupled receptors (GPCRs) classified in to Six Classes (A-F) based on sequence homology and functional similarity by Attwood and Findlay in 1994.

Class AClass BClass CNature Reviews, Drug Discovery

Canonical Structure of Rhodopsin Family receptor

Also known as 7 transmembrane (7 TM) receptors.Couple to G-proteins downstream signal transduction.

Time-line of GPCR structures

Nature Review, 2013In the year 1970, Rhodopsin was the first GPCR purified for biochemical studies.

Challenges in GPCR Structural StudiesLow expression and large amounts needed for crystallization.Lack of long-term stability and conformational flexibility.Inefficient functional solubilization reduces final yield.Inefficient purification leads to aggregation and low yield .Traditional methods do not yield diffracting crystals .

TRENDS in Pharmacological Sciences, 2001Functional diversity of GPCRs

Canonical in structure, but diverse in function. Sense ligands ranging from light, pheromones, hormones, peptides, proteins to neurotransmitters.

Activation Mechanism of GPCRActivation of GPCR required conformational changes involving the global movements of common micro switches conserved in the TM regions.Micro switches include the global rotamer toggling on TM6 or the disruption of an ionic lock between TM3 and TM6, to unlock the G protein-binding site in the intracellular face of the receptors leading to G protein activation.

TRENDS in Pharmacological Sciences, 2009

Major Activation Switches of GPCR

Current Medicinal Chemistry, 2012

G-protein dependent Signaling

Overview of GPCR signaling through G-protein(Gs)

G-protein dependent Signaling

Cell signaling through G-protein (Gq).

GPCR Regulation

Overview of GPCR desensitization by BARK.

Ionic Lock interaction between Arg of TM3 and Glu of TM6 breaks during activation.TRENDS in Pharmacological Sciences, 2007 How to Study the GPCR Activation?

How to Study the GPCR Activation?Calcium AssayTRENDS in Pharmacological Sciences, 2007

How to Study the GPCR Activation?

cAMP AssayInt. J. Mol. Sci. 2014

Studies of GPCR ActivationIP3 AssayInt. J. Mol. Sci. 2014

Why Study GPCR?

TRENDS in Pharmacological Sciences, 2013

Overview of GPCR in human physiology.

ConclusionThe central role of GPCR in human physiology and their diversity of function made the GPCR family one of the prime target for drug discovery.About 30% of current prescribed drugs target GPCRs.So it is very much important to know ligand-Receptor interaction, activation mechanism and signaling process.

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