Allosteric and orthosteric sites in CC chemokine receptor (CCR5), a chimeric receptor approach
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Allosteric and orthosteric sites in CC chemokine receptor (CCR5), a chimeric receptor approach. / Thiele, Stefanie; Steen, Anne; Jensen, Pia C; Mokrosinski, Jacek; Frimurer, Thomas M; Rosenkilde, Mette M.
In: Journal of Biological Chemistry, Vol. 286, No. 43, 2011, p. 37543-54.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Allosteric and orthosteric sites in CC chemokine receptor (CCR5), a chimeric receptor approach
AU - Thiele, Stefanie
AU - Steen, Anne
AU - Jensen, Pia C
AU - Mokrosinski, Jacek
AU - Frimurer, Thomas M
AU - Rosenkilde, Mette M
PY - 2011
Y1 - 2011
N2 - Chemokine receptors play a major role in immune system regulation and have consequently been targets for drug development leading to the discovery of several small molecule antagonists. Given the large size and predominantly extracellular receptor interaction of endogenous chemokines, small molecules often act more deeply in an allosteric mode. However, opposed to the well described molecular interaction of allosteric modulators in class C 7-transmembrane helix (7TM) receptors, the interaction in class A, to which the chemokine receptors belong, is more sparsely described. Using the CCR5 chemokine receptor as a model system, we studied the molecular interaction and conformational interchange required for proper action of various orthosteric chemokines and allosteric small molecules, including the well known CCR5 antagonists TAK-779, SCH-C, and aplaviroc, and four novel CCR5 ago-allosteric molecules. A chimera was successfully constructed between CCR5 and the closely related CCR2 by transferring all extracellular regions of CCR2 to CCR5, i.e. a Trojan horse that resembles CCR2 extracellularly but signals through a CCR5 transmembrane unit. The chimera bound CCR2 (CCL2 and CCL7), but not CCR5 chemokines (CCL3 and CCL5), with CCR2-like high affinities and potencies throughout the CCR5 signaling unit. Concomitantly, high affinity binding of small molecule CCR5 agonists and antagonists was retained in the transmembrane region. Importantly, whereas the agonistic and antagonistic properties were preserved, the allosteric enhancement of chemokine binding was disrupted. In summary, the Trojan horse chimera revealed that orthosteric and allosteric sites could be structurally separated and still act together with transmission of agonism and antagonism across the different receptor units.
AB - Chemokine receptors play a major role in immune system regulation and have consequently been targets for drug development leading to the discovery of several small molecule antagonists. Given the large size and predominantly extracellular receptor interaction of endogenous chemokines, small molecules often act more deeply in an allosteric mode. However, opposed to the well described molecular interaction of allosteric modulators in class C 7-transmembrane helix (7TM) receptors, the interaction in class A, to which the chemokine receptors belong, is more sparsely described. Using the CCR5 chemokine receptor as a model system, we studied the molecular interaction and conformational interchange required for proper action of various orthosteric chemokines and allosteric small molecules, including the well known CCR5 antagonists TAK-779, SCH-C, and aplaviroc, and four novel CCR5 ago-allosteric molecules. A chimera was successfully constructed between CCR5 and the closely related CCR2 by transferring all extracellular regions of CCR2 to CCR5, i.e. a Trojan horse that resembles CCR2 extracellularly but signals through a CCR5 transmembrane unit. The chimera bound CCR2 (CCL2 and CCL7), but not CCR5 chemokines (CCL3 and CCL5), with CCR2-like high affinities and potencies throughout the CCR5 signaling unit. Concomitantly, high affinity binding of small molecule CCR5 agonists and antagonists was retained in the transmembrane region. Importantly, whereas the agonistic and antagonistic properties were preserved, the allosteric enhancement of chemokine binding was disrupted. In summary, the Trojan horse chimera revealed that orthosteric and allosteric sites could be structurally separated and still act together with transmission of agonism and antagonism across the different receptor units.
KW - Allosteric Regulation
KW - Amides
KW - Animals
KW - Benzoates
KW - COS Cells
KW - Cercopithecus aethiops
KW - Chemokines
KW - Cyclic N-Oxides
KW - Humans
KW - Piperazines
KW - Piperidines
KW - Pyridines
KW - Quaternary Ammonium Compounds
KW - Receptors, CCR2
KW - Receptors, CCR5
KW - Recombinant Fusion Proteins
KW - Spiro Compounds
U2 - 10.1074/jbc.M111.243808
DO - 10.1074/jbc.M111.243808
M3 - Journal article
C2 - 21878623
VL - 286
SP - 37543
EP - 37554
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 43
ER -
ID: 38463882