Presented at the Global Medicinal Chemistry and GPCR Summit. To find out more, visit:
www.global-engage.com
Torsten Schöneberg, from the Rudolf Schönheimer Institute of
Biochemistry and University of Leipzig, presents an overview of our current knowledge on aGPCR activation and signal transduction with a focus on the latest findings regarding the interplay between ligand binding, mechanical force, and the tethered agonistic sequence.
Targeting giants - the pharmacology of adhesions GPCRs
1. Targeting Giants
The Pharmacology of Adhesion GPCRs
Torsten Schöneberg
Rudolf Schönheimer Institute
of Biochemistry
Medical Faculty, University of Leipzig
Leipzig, Germany
2. The class of adhesion GPCRs
A
F
lutamate
hodopsin
dhesion
R
G
rizzled/Taste2
ecretinS
lutamateG
R
lutamateG
hodopsinR
lutamateG
A
hodopsinR
lutamateG
dhesionA
hodopsinR
lutamateG
F
dhesionA
hodopsinR
lutamateG
rizzled/Taste2F
dhesionA
hodopsinR
lutamateG
S
rizzled/Taste2F
dhesionA
hodopsinR
lutamateG
ecretinS
F
A
hodopsinR
lutamateG lutamateG
R
lutamateG
hodopsinR
lutamateG
A
R
lutamateG
A
R
lutamateG
F
A
R
(Family C)G
F
A
R
G
S
F
A
R
G
S
F
A
R
G
S ecretin
F
A
R
GG
R
G
R
G
F
R
G
F
R
G
S
F
R
G
A
(Family A)
(Family B)
(Family B)
4. Giants
- > 750 Mio. years old
- N terminus - up to 5,800 aa
- C terminus - up to 450 aa
- numerous interaction partners
- numerous splice variants
Adhesion GPCR are giants among receptors
5. Evolution of aGPCRs and phenotypes in humans
Signatures of recent selection
- GPR133
- GPR110, GPR111, GPR123
- GPR56, GPR64, GPR126
- EMR1, BAI1, CELSR1 …
Kovacs P, Schöneberg T. Handb Exp Pharmacol. 2016;234:179-217.
Selection in human populations
- GPR133
- GPR110, GPR111, GPR113
- GPR115, GPR64, GPR126
- EMR1, EMR3, BAI3 …
QTL/SNP association
GPR133 - height, weight, lipid, glucose, heart rate, myocardial
infarction
GPR126 - weight, lipid, glucose, insulin, height, pulmonary
function
…
7. Adhesion GPCRs couple to G proteins
Bohnekamp J, Schöneberg T. J Biol Chem. 2011;286:41912
SP
P2Y12 N term.
HA tag
FLAG tag
Human GPR133
8. Deletion of the N terminus initiates G-protein coupling
w
t
C
TF
P2Y
12-C
TF
0
200
400
600
800
GPR133
***
***
cAMPaccumulation
[%ofwt]
SP
P2Y12 N term.
HA tag
FLAG tag
SP
HA tag
FLAG tag
CTF P2Y12 CTF
9. Ectodomain as tethered inverse agonist
Hypothetic scenarios of adhesion GPCR activation
Ligand binding
autoprot. cleavage
10. Ectodomain contains a tethered agonist
Hypothetic scenarios of adhesion GPCR activation
Ligand binding
autoprot. cleavage
11. Deletion of the ectodomain activates GPR126
w
t
C
TF
P2Y
12-C
TF
Δ
G
PS-C
TF
P2Y
12-Δ
G
PS-C
TF
0
200
400
600
800
***
***
cAMPaccumulation
[%ofwt]
Liebscher et al. Cell Rep. 2014;9:2018-26.
23. Small Ligands of aGPCRs
Dihydromunduletone Stoveken et al. Mol Pharmacol. 2016;90:214-24.
Antagonist at GPR56 and GPR114
Gupte et al. FEBS Lett. 2012;586:1214-9.
24. cis/trans signaling of adhesion GPCRs
trans signaling
(other partners)
cis signaling
(G proteins)
(and others, e.g. ELMO/Dock)
25. University of Leipzig, Germany
Ines Liebscher
Julia Schön
Lilian Demberg
Caro Wilde
Nina Auerbach
Vera Lede
Christin Schröck
Simone Prömel
Jana Winkler
Antje Müller
Charite Berlin, Germany
Gunnar Kleinau
Vollum Institute
Portland, OR, USA
Kelly Monk
Acknowledgment
http://www.adhesiongpcr.org
26. Presented at the Global Medicinal
Chemistry and GPCR Summit.
To find out more, visit:
www.global-engage.com