7DBL

Acyl-CoA hydrolase MpaH' mutant S139A in complex with MPA

7DBL の概要

• エントリーDOI: 10.2210/pdb7dbl/pdb
• 分子名称: acyl-CoA hydrolase MpaH', MYCOPHENOLIC ACID (3 entities in total)
• 機能のキーワード: peroxisomal acyl-coa hydrolase, mpah', mpa biosynthesis, hydrolase
• 由来する生物種: Penicillium brevicompactum
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 198074.43

構造登録者

Li, S.Y.,You, C. (登録日: 2020-10-20, 公開日: 2021-04-28, 最終更新日: 2023-11-29)

主引用文献

You, C.,Li, F.,Zhang, X.,Ma, L.,Zhang, Y.Z.,Zhang, W.,Li, S.
Structural basis for substrate specificity of the peroxisomal acyl-CoA hydrolase MpaH' involved in mycophenolic acid biosynthesis.
Febs J., 288:5768-5780, 2021

PubMed Abstract: Mycophenolic acid (MPA) is a fungal natural product and first-line immunosuppressive drug for organ transplantations and autoimmune diseases. In the compartmentalized biosynthesis of MPA, the acyl-coenzyme A (CoA) hydrolase MpaH' located in peroxisomes catalyzes the highly specific hydrolysis of MPA-CoA to produce the final product MPA. The strict substrate specificity of MpaH' not only averts undesired hydrolysis of various cellular acyl-CoAs, but also prevents MPA-CoA from further peroxisomal β-oxidation catabolism. To elucidate the structural basis for this important property, in this study, we solve the crystal structures of the substrate-free form of MpaH' and the MpaH' mutant in complex with the product MPA. The MpaH' structure reveals a canonical α/β-hydrolase fold with an unusually large cap domain and a rare location of the acidic residue D163 of catalytic triad after strand β6. MpaH' also forms an atypical dimer with the unique C-terminal helices α13 and α14 arming the cap domain of the other protomer and indirectly participating in the substrate binding. With these characteristics, we propose that MpaH' and its homologs form a new subfamily of α/β hydrolase fold protein. The crystal structure of MpaH' /MPA complex and the modeled structure of MpaH'/MPA-CoA, together with the structure-guided mutagenesis analysis and isothermal titration calorimetry (ITC) measurements, provide important mechanistic insights into the high substrate specificity of MpaH'.

PubMed: 33843134
DOI: 10.1111/febs.15874

実験手法

X-RAY DIFFRACTION (1.84 Å)