8DPB

MeaB in complex with the cobalamin-binding domain of its target mutase with GMPPCP bound

8DPB の概要

• エントリーDOI: 10.2210/pdb8dpb/pdb
• 分子名称: Methylmalonyl-CoA mutase accessory protein, Methylmalonyl-CoA mutase, alpha subunit, PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER, ... (6 entities in total)
• 機能のキーワード: metalloenzyme maturation, complex, g-protein chaperone, cobalamin, chaperone
• 由来する生物種: Methylorubrum extorquens AM1; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 110725.82

構造登録者

Vaccaro, F.A.,Born, D.A.,Drennan, C.L. (登録日: 2022-07-15, 公開日: 2023-03-01, 最終更新日: 2024-04-03)

主引用文献

Vaccaro, F.A.,Born, D.A.,Drennan, C.L.
Structure of metallochaperone in complex with the cobalamin-binding domain of its target mutase provides insight into cofactor delivery.
Proc.Natl.Acad.Sci.USA, 120:e2214085120-e2214085120, 2023

PubMed Abstract: G-protein metallochaperone MeaB in bacteria [methylmalonic aciduria type A (MMAA) in humans] is responsible for facilitating the delivery of adenosylcobalamin (AdoCbl) to methylmalonyl-CoA mutase (MCM), the only AdoCbl-dependent enzyme in humans. Genetic defects in the switch III region of MMAA lead to the genetic disorder methylmalonic aciduria in which the body is unable to process certain lipids. Here, we present a crystal structure of MeaB bound to a nonhydrolyzable guanosine triphosphate (GTP) analog guanosine-5'-[(β,γ)-methyleno]triphosphate (GMPPCP) with the Cbl-binding domain of its target mutase enzyme (MCM). This structure provides an explanation for the stimulation of the GTP hydrolyase activity of MeaB afforded by target protein binding. We find that upon MCM association, one protomer of the MeaB dimer rotates ~180°, such that the inactive state of MeaB is converted to an active state in which the nucleotide substrate is now surrounded by catalytic residues. Importantly, it is the switch III region that undergoes the largest change, rearranging to make direct contacts with the terminal phosphate of GMPPCP. These structural data additionally provide insights into the molecular basis by which this metallochaperone contributes to AdoCbl delivery without directly binding the cofactor. Our data suggest a model in which GTP-bound MeaB stabilizes a conformation of MCM that is open for AdoCbl insertion, and GTP hydrolysis, as signaled by switch III residues, allows MCM to close and trap its cofactor. Substitutions of switch III residues destabilize the active state of MeaB through loss of protein:nucleotide and protein:protein interactions at the dimer interface, thus uncoupling GTP hydrolysis from AdoCbl delivery.

PubMed: 36787360
DOI: 10.1073/pnas.2214085120

実験手法

X-RAY DIFFRACTION (2.72 Å)