PMID- 35034430
OWN - NLM
STAT- MEDLINE
DCOM- 20220407
LR  - 20220729
IS  - 1860-7187 (Electronic)
IS  - 1860-7179 (Print)
IS  - 1860-7179 (Linking)
VI  - 17
IP  - 7
DP  - 2022 Apr 5
TI  - Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the 
      Nucleotide Receptor P2Y(6).
PG  - e202100683
LID - 10.1002/cmdc.202100683 [doi]
LID - e202100683
AB  - Cyclooxygenase-2 catalyzes the biosynthesis of prostaglandins from arachidonic 
      acid and the biosynthesis of prostaglandin glycerol esters (PG-Gs) from 
      2-arachidonoylglycerol. PG-Gs are mediators of several biological actions such as 
      macrophage activation, hyperalgesia, synaptic plasticity, and intraocular 
      pressure. Recently, the human UDP receptor P2Y(6) was identified as a target for 
      the prostaglandin E2 glycerol ester (PGE(2) -G). Here, we show that UDP and 
      PGE(2) -G are evolutionary conserved endogenous agonists at vertebrate P2Y(6) 
      orthologs. Using sequence comparison of P2Y(6) orthologs, homology modeling, and 
      ligand docking studies, we proposed several receptor positions participating in 
      agonist binding. Site-directed mutagenesis and functional analysis of these 
      P2Y(6) mutants revealed that both UDP and PGE(2) -G share in parts one 
      ligand-binding site. Thus, the convergent signaling of these two chemically very 
      different agonists has already been manifested in the evolutionary design of the 
      ligand-binding pocket.
CI  - (c) 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.
FAU - Zimmermann, Anne
AU  - Zimmermann A
AD  - Rudolf Schonheimer Institute of Biochemistry, Medical Faculty, University of 
      Leipzig, 04103, Leipzig, Germany.
FAU - Vu, Oanh
AU  - Vu O
AD  - Department of Chemistry, Center for Structural Biology, Vanderbilt University, TN 
      37232-8725, Nashville, USA.
FAU - Bruser, Antje
AU  - Bruser A
AD  - Rudolf Schonheimer Institute of Biochemistry, Medical Faculty, University of 
      Leipzig, 04103, Leipzig, Germany.
FAU - Sliwoski, Gregory
AU  - Sliwoski G
AD  - Department of Biomedical Informatics, Vanderbilt University School of Medicine, 
      TN 37232-8725, Nashville, USA.
FAU - Marnett, Lawrence J
AU  - Marnett LJ
AD  - Vanderbilt Institute of Chemical Biology, Vanderbilt University School of 
      Medicine, TN 37232-0146, Nashville, USA.
FAU - Meiler, Jens
AU  - Meiler J
AD  - Department of Chemistry, Center for Structural Biology, Vanderbilt University, TN 
      37232-8725, Nashville, USA.
AD  - Institute of Drug Discovery, Faculty of Medicine, University of Leipzig, 04103, 
      Leipzig, Germany.
FAU - Schoneberg, Torsten
AU  - Schoneberg T
AUID- ORCID: 0000-0001-5313-0237
AD  - Rudolf Schonheimer Institute of Biochemistry, Medical Faculty, University of 
      Leipzig, 04103, Leipzig, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220128
PL  - Germany
TA  - ChemMedChem
JT  - ChemMedChem
JID - 101259013
RN  - 0 (Nucleotides)
RN  - 0 (prostaglandin E2 glyceryl ester)
RN  - 58-98-0 (Uridine Diphosphate)
RN  - K7Q1JQR04M (Dinoprostone)
SB  - IM
MH  - Binding Sites
MH  - *Dinoprostone/analogs & derivatives
MH  - Humans
MH  - *Nucleotides
MH  - Uridine Diphosphate
PMC - PMC9305961
OTO - NOTNLM
OT  - G protein-coupled receptors
OT  - PGE2-G
OT  - UDP
OT  - binding site
OT  - site-directed mutagenesis
COIS- The authors declare no conflict of interest.
EDAT- 2022/01/17 06:00
MHDA- 2022/04/08 06:00
PMCR- 2022/07/22
CRDT- 2022/01/16 21:25
PHST- 2022/01/14 00:00 [revised]
PHST- 2021/10/29 00:00 [received]
PHST- 2022/01/17 06:00 [pubmed]
PHST- 2022/04/08 06:00 [medline]
PHST- 2022/01/16 21:25 [entrez]
PHST- 2022/07/22 00:00 [pmc-release]
AID - CMDC202100683 [pii]
AID - 10.1002/cmdc.202100683 [doi]
PST - ppublish
SO  - ChemMedChem. 2022 Apr 5;17(7):e202100683. doi: 10.1002/cmdc.202100683. Epub 2022 
      Jan 28.