TY - JOUR
T1 - Structural basis for selective inhibition of human serine hydroxymethyltransferase by secondary bile acid conjugate
AU - Ota, Tomoki
AU - Senoo, Akinobu
AU - Shirakawa, Masumi
AU - Nonaka, Hiroshi
AU - Saito, Yutaro
AU - Ito, Sho
AU - Ueno, Go
AU - Nagatoishi, Satoru
AU - Tsumoto, Kouhei
AU - Sando, Shinsuke
N1 - Funding Information:
S.S. acknowledges financial support from CREST ( JPMJCR13L4 ), Japan Science and Technology Agency , and partly from JSPS KAKENHI ( 19H00919 ). K.T. acknowledges financial support from JSPS ( JP19H05766 and JM16H02420 ). S.N. acknowledges financial support from JSPS ( JP18H02082 ). This research was supported by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED ( JP19am0101001 and JP19am0101094 ). We thank the staffs of the SPring-8 (BL26B2) for excellent technical support. Plasmid for recombinant hSHMT2 including A269T mutation was a gift from Prof. C. Arrowsmith of University of Toronto, Canada (Addgene plasmid # 25479).
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/2/19
Y1 - 2021/2/19
N2 - Bile acids are metabolites of cholesterol that facilitate lipid digestion and absorption in the small bowel. Bile acids work as agonists of receptors to regulate their own metabolism. Bile acids also regulate other biological systems such as sugar metabolism, intestinal multidrug resistance, and adaptive immunity. However, numerous physiological roles of bile acids remain undetermined. In this study, we solved the crystal structure of human serine hydroxymethyltransferase (hSHMT) in complex with an endogenous secondary bile acid glycine conjugate. The specific interaction between hSHMT and the ligand was demonstrated using mutational analyses, biophysical measurements, and structure-activity relationship studies, suggesting that secondary bile acid conjugates may act as modulators of SHMT activity.
AB - Bile acids are metabolites of cholesterol that facilitate lipid digestion and absorption in the small bowel. Bile acids work as agonists of receptors to regulate their own metabolism. Bile acids also regulate other biological systems such as sugar metabolism, intestinal multidrug resistance, and adaptive immunity. However, numerous physiological roles of bile acids remain undetermined. In this study, we solved the crystal structure of human serine hydroxymethyltransferase (hSHMT) in complex with an endogenous secondary bile acid glycine conjugate. The specific interaction between hSHMT and the ligand was demonstrated using mutational analyses, biophysical measurements, and structure-activity relationship studies, suggesting that secondary bile acid conjugates may act as modulators of SHMT activity.
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U2 - 10.1016/j.isci.2021.102036
DO - 10.1016/j.isci.2021.102036
M3 - Article
AN - SCOPUS:85099608280
VL - 24
JO - iScience
JF - iScience
SN - 2589-0042
IS - 2
M1 - 102036
ER -