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Crystal structure of an apo 7α-hydroxysteroid dehydrogenase reveals key structural changes induced by substrate and co-factor binding

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Title
Crystal structure of an apo 7α-hydroxysteroid dehydrogenase reveals key structural changes induced by substrate and co-factor binding
Other Titles
7α-hydroxysteroid dehydrogenase 효소의 구조분석을 통한 조효소와 기질 결합에 의한 구조변화 연구
Authors
Kim, Ki-Hwa
Lee, Chang Woo
Pardhe, Bashu Dev
Hwang, Jisub
Do, Hackwon
Lee, Yung Mi
Lee, Jun Hyuck
Oh, Tae-Jin
Subject
Biochemistry & Molecular BiologyEndocrinology & Metabolism
Keywords
Crystal structureConformational change7 alpha-hydroxysteroid dehydrogenaseX-ray crystallography
Issue Date
2021-09
Citation
Ki-Hwa Kim, et al. 2021. "Crystal structure of an apo 7α-hydroxysteroid dehydrogenase reveals key structural changes induced by substrate and co-factor binding". JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 212(1): 105945-105945.
Abstract
7α-Hydroxysteroid dehydrogenase (7α-HSDH) catalyzes the dehydrogenation of a hydroxyl group at the 7α position in steroid substrates using NAD+ or NADP+ as a co-factor. Although studies have determined the binary and ternary complex structures, detailed structural changes induced by ligand and co-factor binding remain unclear, because ligand-free structures are not yet available. Here, we present the crystal structure of apo 7α-HSDH from Escherichia coli (Eco-7α-HSDH) at 2.7 A resolution. We found that the apo form undergoes substantial conformational changes in the β4-α4 loop, α7-α8 helices, and C-terminus loop among the four subunits comprising the tetramer. Furthermore, a comparison of the apo structure with the binary (NAD+)-complex and ternary (NADH and 7-oxoglycochenodeoxycholic acid)-complex Eco-7α-HSDH structures revealed that only the ternary-complex structure has a fully closed conformation, whereas the binary-complex and apo structures have a semi-closed or open conformation. This open-to-closed transition forces several catalytically important residues (S146, Y159, and K163) into correct positions for catalysis. To confirm the catalytic activity, we used alcohol dehydrogenase for NAD+ regeneration to allow efficient conversion of chenodeoxycholic acid to 7-ketolithocholic acid by Eco-7α-HSDH. These findings demonstrate that apo Eco-7α-HSDH exhibits intrinsically flexible characteristics with an open conformation. This structural information provides novel insight into the 7α-HSDH reaction mechanism.
URI
https://repository.kopri.re.kr/handle/201206/12981
DOI
http://dx.doi.org/10.1016/j.jsbmb.2021.105945
Type
Article
Station
해당사항없음
Indexed
SCIE
Appears in Collections  
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