Premium
Structural analysis of cofactor binding for a prolyl 4‐hydroxylase from the pathogenic bacterium Bacillus anthracis
Author(s) -
Schnicker Nicholas J.,
Dey Mishtu
Publication year - 2016
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.374
H-Index - 138
ISSN - 2059-7983
DOI - 10.1107/s2059798316004198
Subject(s) - bacillus anthracis , cofactor , enzyme , hydroxylation , chemistry , active site , stereochemistry , biochemistry , hydroxyproline , substrate (aquarium) , binding site , ternary complex , bacteria , biology , ecology , genetics
The prolyl 4‐hydroxylases (P4Hs) are mononuclear nonheme iron enzymes that catalyze the formation of 4 R ‐hydroxyproline from many different substrates, with various biological implications. P4H is a key player in collagen accumulation, which has implications in fibrotic disorders. The stabilization of collagen triple‐helical structure via prolyl hydroxylation is the rate‐limiting step in collagen biosynthesis, and therefore P4H has been extensively investigated as a potential therapeutic target of fibrotic disease. Understanding how these enzymes recognize cofactors and substrates is important and will aid in the future design of inhibitors of P4H. In this article, X‐ray crystal structures of a metallocofactor‐ and α‐ketoglutarate (αKG)‐bound form of P4H from Bacillus anthracis (BaP4H) are reported. Structures of BaP4H were solved at 1.63 and 2.35 Å resolution and contained a cadmium ion and αKG bound in the active site. The αKG–Cd–BaP4H ternary complex reveals conformational changes of conserved residues upon the binding of metal ion and αKG, resulting in a closed active‐site configuration required for dioxygen, substrate binding and catalysis.