8DYJ
Crystal structure of human methylmalonyl-CoA mutase in complex with ADP and cob(II)alamin
Summary for 8DYJ
| Entry DOI | 10.2210/pdb8dyj/pdb |
| Descriptor | Methylmalonyl-CoA mutase, mitochondrial, COBALAMIN, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total) |
| Functional Keywords | cobalamin, adp, mutase, vitamin b12, isomerase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 86593.38 |
| Authors | Mascarenhas, R.N.,Gouda, H.,Banerjee, R. (deposition date: 2022-08-04, release date: 2023-07-12, Last modification date: 2023-10-25) |
| Primary citation | Gouda, H.,Mascarenhas, R.,Ruetz, M.,Yaw, M.,Banerjee, R. Bivalent molecular mimicry by ADP protects metal redox state and promotes coenzyme B 12 repair. Proc.Natl.Acad.Sci.USA, 120:e2220677120-e2220677120, 2023 Cited by PubMed Abstract: Control over transition metal redox state is essential for metalloprotein function and can be achieved via coordination chemistry and/or sequestration from bulk solvent. Human methylmalonyl-Coenzyme A (CoA) mutase (MCM) catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA using 5'-deoxyadenosylcobalamin (AdoCbl) as a metallocofactor. During catalysis, the occasional escape of the 5'-deoxyadenosine (dAdo) moiety leaves the cob(II)alamin intermediate stranded and prone to hyperoxidation to hydroxocobalamin, which is recalcitrant to repair. In this study, we have identified the use of bivalent molecular mimicry by ADP, coopting the 5'-deoxyadenosine and diphosphate moieties in the cofactor and substrate, respectively, to protect against cob(II)alamin overoxidation on MCM. Crystallographic and electron paramagnetic resonance (EPR) data reveal that ADP exerts control over the metal oxidation state by inducing a conformational change that seals off solvent access, rather than by switching five-coordinate cob(II)alamin to the more air stable four-coordinate state. Subsequent binding of methylmalonyl-CoA (or CoA) promotes cob(II)alamin off-loading from MCM to adenosyltransferase for repair. This study identifies an unconventional strategy for controlling metal redox state by an abundant metabolite to plug active site access, which is key to preserving and recycling a rare, but essential, metal cofactor. PubMed: 36888659DOI: 10.1073/pnas.2220677120 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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