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G-Protein Coupled Receptor (GPCR)
BHARAT KUMAR
OUTLINE
Introduction
Classification
Structure
Activation Mechanism
Signaling
Conclusion
INTRODUCTION
 GPCR 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, 2005
 GPCR 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.
Classification
Annu Rev Pharmacol Toxicol, 2013
Difference Between Subfamilies
 The G protein–coupled receptors
(GPCRs) classified in to Six Classes
(A-F) based on sequence homology
and functional similarity by Attwood
and Findlay in 1994.
Class A
Class B
Class C
Nature 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, 2013
 In the year 1970, Rhodopsin
was the first GPCR purified
for biochemical studies.
Challenges in GPCR Structural Studies
 Low 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, 2001
Functional diversity of GPCRs
 Canonical in structure, but diverse in function. Sense ligands ranging from
light, pheromones, hormones, peptides, proteins to neurotransmitters.
Activation Mechanism of GPCR
 Activation 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 Assay
TRENDS in Pharmacological Sciences, 2007
How to Study the GPCR Activation?
 cAMP Assay
Int. J. Mol. Sci. 2014
Studies of GPCR Activation
 IP3 Assay
Int. J. Mol. Sci. 2014
Why Study GPCR?
TRENDS in Pharmacological Sciences, 2013
 Overview of GPCR in human physiology.
Conclusion
 The 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.
Thank You

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G protein coupled receptor(gpcr)

  • 1. G-Protein Coupled Receptor (GPCR) BHARAT KUMAR
  • 3. INTRODUCTION  GPCR 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.
  • 4. GPCR “Tree of Life” Mol Pharmacol, 2005  GPCR is the largest known class of biologically important transmembrane proteins conserved throughout the evolution.
  • 5.  Later in 2003, GPCR classified in to Five families according to the GRAFS system : Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin) by Fredriksson. Classification Annu Rev Pharmacol Toxicol, 2013
  • 6. Difference Between Subfamilies  The G protein–coupled receptors (GPCRs) classified in to Six Classes (A-F) based on sequence homology and functional similarity by Attwood and Findlay in 1994. Class A Class B Class C Nature Reviews, Drug Discovery
  • 7. Canonical Structure of Rhodopsin Family receptor  Also known as 7 transmembrane (7 TM) receptors.  Couple to G-proteins  downstream signal transduction.
  • 8. Time-line of GPCR structures Nature Review, 2013  In the year 1970, Rhodopsin was the first GPCR purified for biochemical studies.
  • 9. Challenges in GPCR Structural Studies  Low 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 .
  • 10. TRENDS in Pharmacological Sciences, 2001 Functional diversity of GPCRs  Canonical in structure, but diverse in function. Sense ligands ranging from light, pheromones, hormones, peptides, proteins to neurotransmitters.
  • 11. Activation Mechanism of GPCR  Activation 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
  • 12. Major Activation Switches of GPCR Current Medicinal Chemistry, 2012
  • 13. G-protein dependent Signaling  Overview of GPCR signaling through G-protein(Gs)
  • 14. G-protein dependent Signaling  Cell signaling through G-protein (Gq).
  • 15. GPCR Regulation  Overview of GPCR desensitization by BARK.
  • 16.  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?
  • 17. How to Study the GPCR Activation?  Calcium Assay TRENDS in Pharmacological Sciences, 2007
  • 18. How to Study the GPCR Activation?  cAMP Assay Int. J. Mol. Sci. 2014
  • 19. Studies of GPCR Activation  IP3 Assay Int. J. Mol. Sci. 2014
  • 20. Why Study GPCR? TRENDS in Pharmacological Sciences, 2013  Overview of GPCR in human physiology.
  • 21. Conclusion  The 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.