8DYL

Crystal structure of human methylmalonyl-CoA mutase bound to aquocobalamin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

Bivalent molecular mimicry by ADP protects metal redox state and promotes coenzyme B 12 repair.

Gouda, H.Mascarenhas, R.Ruetz, M.Yaw, M.Banerjee, R.

(2023) Proc Natl Acad Sci U S A 120: e2220677120-e2220677120

  • DOI: https://doi.org/10.1073/pnas.2220677120
  • Primary Citation of Related Structures:  
    8DYJ, 8DYL

  • 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.


  • Organizational Affiliation

    Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Methylmalonyl-CoA mutase, mitochondrialA [auth B]762Homo sapiensMutation(s): 0 
Gene Names: MMUTMUT
EC: 5.4.99.2
UniProt & NIH Common Fund Data Resources
Find proteins for P22033 (Homo sapiens)
Explore P22033 
Go to UniProtKB:  P22033
PHAROS:  P22033
GTEx:  ENSG00000146085 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP22033
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.377α = 90
b = 136.07β = 90
c = 196.015γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
DIALSdata reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesRO1-DK45776
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesK99-GM1434820

Revision History  (Full details and data files)

  • Version 1.0: 2023-07-12
    Type: Initial release
  • Version 1.1: 2023-08-23
    Changes: Data collection, Database references
  • Version 1.2: 2023-10-25
    Changes: Refinement description