PMID- 35809897
OWN - NLM
STAT- MEDLINE
DCOM- 20220817
LR  - 20220902
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 102
IP  - 3
DP  - 2022 Sep
TI  - Effects of Small Molecule Ligands on ACKR3 Receptors.
PG  - 128-138
LID - 10.1124/molpharm.121.000295 [doi]
AB  - Chemokines such as stromal derived factor 1 and their G protein coupled receptors 
      are well-known regulators of the development and functions of numerous tissues. 
      C-X-C motif chemokine ligand 12 (CXCL12) has two receptors: C-X-C chemokine motif 
      receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3). ACKR3 has been 
      described as an atypical "biased" receptor because it does not appear to signal 
      through G proteins and, instead, signals solely through the beta-arrestin pathway. 
      In support of this conclusion, we have shown that ACKR3 is unable to signal 
      through any of the known mammalian G (alpha) isoforms and have generated a 
      comprehensive map of the G (alpha) activation by CXCL12/CXCR4. We also synthesized a 
      series of small molecule ligands which acted as selective agonists for ACKR3 as 
      assessed by their ability to recruit beta-arrestin to the receptor. Using select 
      point mutations, we studied the molecular characteristics that determine the 
      ability of small molecules to activate ACKR3 receptors, revealing a key role for 
      the deeper binding pocket composed of residues in the transmembrane domains of 
      ACKR3. The development of more selective ACKR3 ligands should allow us to better 
      appreciate the unique roles of ACKR3 in the CXCL12/CXCR4/ACKR3-signaling axis and 
      better understand the structural determinants for ACKR3 activation. SIGNIFICANCE 
      STATEMENT: We are interested in the signaling produced by the G protein coupled 
      receptor atypical chemokine receptor 3 (ACKR3), which signals atypically. In this 
      study, novel selective ligands for ACKR3 were discovered and the site of 
      interactions between these small molecules and ACKR3 was defined. This work will 
      help to better understand the unique signaling roles of ACKR3.
CI  - Copyright (c) 2022 by The Author(s).
FAU - Hopkins, Brittany E
AU  - Hopkins BE
AD  - Department of Pharmacology (B.E.H., D.R., G.E.S., R.J.M.) and Robert H. Lurie 
      Comprehensive Cancer Center (G.E.S.), Northwestern University, Chicago Illinois; 
      Department of Chemistry (G.E.S.) and Center for Molecular Innovation and Drug 
      Discovery (I.D.I., W.L., N.M., G.E.S.), Northwestern University, Evanston 
      Illinois; and Department of Neuroscience, The Scripps Research Institute Florida, 
      Jupiter, Florida (I.M., K.A.M.).
FAU - Masuho, Ikuo
AU  - Masuho I
AD  - Department of Pharmacology (B.E.H., D.R., G.E.S., R.J.M.) and Robert H. Lurie 
      Comprehensive Cancer Center (G.E.S.), Northwestern University, Chicago Illinois; 
      Department of Chemistry (G.E.S.) and Center for Molecular Innovation and Drug 
      Discovery (I.D.I., W.L., N.M., G.E.S.), Northwestern University, Evanston 
      Illinois; and Department of Neuroscience, The Scripps Research Institute Florida, 
      Jupiter, Florida (I.M., K.A.M.).
FAU - Ren, Dongjun
AU  - Ren D
AD  - Department of Pharmacology (B.E.H., D.R., G.E.S., R.J.M.) and Robert H. Lurie 
      Comprehensive Cancer Center (G.E.S.), Northwestern University, Chicago Illinois; 
      Department of Chemistry (G.E.S.) and Center for Molecular Innovation and Drug 
      Discovery (I.D.I., W.L., N.M., G.E.S.), Northwestern University, Evanston 
      Illinois; and Department of Neuroscience, The Scripps Research Institute Florida, 
      Jupiter, Florida (I.M., K.A.M.).
FAU - Iyamu, Iredia D
AU  - Iyamu ID
AD  - Department of Pharmacology (B.E.H., D.R., G.E.S., R.J.M.) and Robert H. Lurie 
      Comprehensive Cancer Center (G.E.S.), Northwestern University, Chicago Illinois; 
      Department of Chemistry (G.E.S.) and Center for Molecular Innovation and Drug 
      Discovery (I.D.I., W.L., N.M., G.E.S.), Northwestern University, Evanston 
      Illinois; and Department of Neuroscience, The Scripps Research Institute Florida, 
      Jupiter, Florida (I.M., K.A.M.).
FAU - Lv, Wei
AU  - Lv W
AD  - Department of Pharmacology (B.E.H., D.R., G.E.S., R.J.M.) and Robert H. Lurie 
      Comprehensive Cancer Center (G.E.S.), Northwestern University, Chicago Illinois; 
      Department of Chemistry (G.E.S.) and Center for Molecular Innovation and Drug 
      Discovery (I.D.I., W.L., N.M., G.E.S.), Northwestern University, Evanston 
      Illinois; and Department of Neuroscience, The Scripps Research Institute Florida, 
      Jupiter, Florida (I.M., K.A.M.).
FAU - Malik, Neha
AU  - Malik N
AD  - Department of Pharmacology (B.E.H., D.R., G.E.S., R.J.M.) and Robert H. Lurie 
      Comprehensive Cancer Center (G.E.S.), Northwestern University, Chicago Illinois; 
      Department of Chemistry (G.E.S.) and Center for Molecular Innovation and Drug 
      Discovery (I.D.I., W.L., N.M., G.E.S.), Northwestern University, Evanston 
      Illinois; and Department of Neuroscience, The Scripps Research Institute Florida, 
      Jupiter, Florida (I.M., K.A.M.).
FAU - Martemyanov, Kirill A
AU  - Martemyanov KA
AD  - Department of Pharmacology (B.E.H., D.R., G.E.S., R.J.M.) and Robert H. Lurie 
      Comprehensive Cancer Center (G.E.S.), Northwestern University, Chicago Illinois; 
      Department of Chemistry (G.E.S.) and Center for Molecular Innovation and Drug 
      Discovery (I.D.I., W.L., N.M., G.E.S.), Northwestern University, Evanston 
      Illinois; and Department of Neuroscience, The Scripps Research Institute Florida, 
      Jupiter, Florida (I.M., K.A.M.).
FAU - Schiltz, Gary E
AU  - Schiltz GE
AD  - Department of Pharmacology (B.E.H., D.R., G.E.S., R.J.M.) and Robert H. Lurie 
      Comprehensive Cancer Center (G.E.S.), Northwestern University, Chicago Illinois; 
      Department of Chemistry (G.E.S.) and Center for Molecular Innovation and Drug 
      Discovery (I.D.I., W.L., N.M., G.E.S.), Northwestern University, Evanston 
      Illinois; and Department of Neuroscience, The Scripps Research Institute Florida, 
      Jupiter, Florida (I.M., K.A.M.).
FAU - Miller, Richard J
AU  - Miller RJ
AD  - Department of Pharmacology (B.E.H., D.R., G.E.S., R.J.M.) and Robert H. Lurie 
      Comprehensive Cancer Center (G.E.S.), Northwestern University, Chicago Illinois; 
      Department of Chemistry (G.E.S.) and Center for Molecular Innovation and Drug 
      Discovery (I.D.I., W.L., N.M., G.E.S.), Northwestern University, Evanston 
      Illinois; and Department of Neuroscience, The Scripps Research Institute Florida, 
      Jupiter, Florida (I.M., K.A.M.) r-miller10@northwestern.edu.
LA  - eng
GR  - P30 CA060553/CA/NCI NIH HHS/United States
GR  - R01 CA189074/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220709
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Ligands)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (beta-Arrestins)
SB  - IM
MH  - Animals
MH  - *Chemokine CXCL12/metabolism
MH  - Ligands
MH  - Mammals/metabolism
MH  - *Receptors, CXCR4/metabolism
MH  - Signal Transduction
MH  - beta-Arrestins/metabolism
PMC - PMC9393849
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article.
EDAT- 2022/07/10 06:00
MHDA- 2022/08/18 06:00
PMCR- 2022/09/01
CRDT- 2022/07/09 20:42
PHST- 2021/04/03 00:00 [received]
PHST- 2022/05/31 00:00 [accepted]
PHST- 2022/07/10 06:00 [pubmed]
PHST- 2022/08/18 06:00 [medline]
PHST- 2022/07/09 20:42 [entrez]
PHST- 2022/09/01 00:00 [pmc-release]
AID - molpharm.121.000295 [pii]
AID - MOL_AR2021000295 [pii]
AID - 10.1124/molpharm.121.000295 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2022 Sep;102(3):128-138. doi: 10.1124/molpharm.121.000295. Epub 
      2022 Jul 9.