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Cover Picture: Structure–Activity Relationship Studies of the Cyclic Depsipeptide Natural Product YM‐254890, Targeting the G q Protein (ChemMedChem 11/2017)
Author(s) -
Zhang Hang,
Xiong XiaoFeng,
Boesgaard Michael W.,
Underwood Christina R.,
BräunerOsborne Hans,
Strømgaard Kristian
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Reports
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700313
Subject(s) - depsipeptide , natural product , chemistry , stereochemistry , protein data bank (rcsb pdb) , gq alpha subunit , structure–activity relationship , signal transduction , biochemistry , g protein , in vitro
The front cover picture shows the X‐ray crystal structure of the natural product, cyclic depsipeptide YM‐254890 bound to the Gα i/q protein (PDB: 3AH8). YM‐254890, together with its structural analogue FR900359, is the only known inhibitor of G q proteins. The inhibition of G q by YM‐254890 is achieved by stabilizing an inactive GDP‐bound form of G q , which then blocks the fundamental GDP/GTP exchange of the G protein. By performing structure–activity relationship studies of YM‐254890 focusing N Me‐Ala and Ala, we discovered three new selective G q signaling inhibitors ( YM‐13 , YM‐14 , and YM‐18 ) which show potencies equivalent with that of the natural compound YM‐254890, while YM‐14 was the most potent analogue. These results provide pertinent information for understanding the G q inhibitory mechanism. Importantly, they also provide a pathway for the development of labeled YM‐254890 analogues. More information can be found in the Communication by Kristian Strømgaard et al. on page 830 in Issue 11, 2017 (DOI: 10.1002/cmdc.201700155).