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