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- PDB-9ssv: Human Methionine Synthase With Methylcobalamin, Activation Domain... -

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Basic information

Entry
Database: PDB / ID: 9ssv
TitleHuman Methionine Synthase With Methylcobalamin, Activation Domain From Full-Length
ComponentsMethionine synthase
KeywordsTRANSFERASE / Methionine / Folate / Cobalamin
Function / homology
Function and homology information


Defective MTRR causes HMAE / Defective MTR causes HMAG / sulfur amino acid metabolic process / Sulfur amino acid metabolism / Cobalamin (Cbl) metabolism / cobalamin metabolic process / methionine synthase / methionine synthase activity / homocysteine metabolic process / Methylation ...Defective MTRR causes HMAE / Defective MTR causes HMAG / sulfur amino acid metabolic process / Sulfur amino acid metabolism / Cobalamin (Cbl) metabolism / cobalamin metabolic process / methionine synthase / methionine synthase activity / homocysteine metabolic process / Methylation / cobalamin binding / tetrahydrofolate metabolic process / : / axon regeneration / RHOH GTPase cycle / response to axon injury / cellular response to nitric oxide / nervous system development / methylation / zinc ion binding / cytosol
Similarity search - Function
Vitamin B12-dependent methionine synthase, activation domain / Vitamin B12 dependent methionine synthase, activation domain / AdoMet activation domain profile. / Cobalamin-dependent methionine synthase / Methionine synthase, B12-binding domain / Vitamin B12-dependent methionine synthase, activation domain superfamily / B12-binding N-terminal domain profile. / B12 binding domain / Homocysteine-binding domain / Homocysteine-binding domain superfamily ...Vitamin B12-dependent methionine synthase, activation domain / Vitamin B12 dependent methionine synthase, activation domain / AdoMet activation domain profile. / Cobalamin-dependent methionine synthase / Methionine synthase, B12-binding domain / Vitamin B12-dependent methionine synthase, activation domain superfamily / B12-binding N-terminal domain profile. / B12 binding domain / Homocysteine-binding domain / Homocysteine-binding domain superfamily / Homocysteine S-methyltransferase / Homocysteine-binding domain profile. / : / Cobalamin (vitamin B12)-binding module, cap domain / B12 binding domain / Methionine synthase domain / B12 binding domain / Cobalamin-binding domain superfamily / B12-binding domain profile. / Cobalamin (vitamin B12)-binding domain / Pterin-binding domain / Pterin binding enzyme / Pterin-binding domain profile. / Dihydropteroate synthase-like
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsFerreira, D.S.M. / Yue, W.W. / McCorvie, T.J.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust092809/Z/10/Z United Kingdom
CitationJournal: Nat Commun / Year: 2026
Title: Structural insights into cobalamin loading and reactivation of human methionine synthase.
Authors: Douglas S M Ferreira / Katie McLennan / Calum Diamond / Melanie Vollmar / Wasim Kiyani / D Sean Froese / Jola Kopec / Henry J Bailey / Rod Chalk / Arnaud Baslé / Jonathan M Elkins / Jesse A ...Authors: Douglas S M Ferreira / Katie McLennan / Calum Diamond / Melanie Vollmar / Wasim Kiyani / D Sean Froese / Jola Kopec / Henry J Bailey / Rod Chalk / Arnaud Baslé / Jonathan M Elkins / Jesse A Coker / Wyatt W Yue / Thomas J McCorvie /
Abstract: Human methionine synthase (MTR) is an essential enzyme of one carbon metabolism. Consisting of a catalytic N-half and a cobalamin binding C-half, MTR utilises this intricate organometallic cofactor ...Human methionine synthase (MTR) is an essential enzyme of one carbon metabolism. Consisting of a catalytic N-half and a cobalamin binding C-half, MTR utilises this intricate organometallic cofactor in the methyl transfer from methyltetrahydrofolate to homocysteine producing methionine. Cobalamin loading into MTR, and its subsequent activation, requires methylmalonic aciduria and homocystinuria Type D (MMADHC) protein and methionine synthase reductase (MTRR), respectively. However, the molecular basis of cobalamin binding and activation of human MTR aided by MMADHC and MTRR remains unknown. Here, using cryo-electron microscopy, we determine structures of human MTR in its apo, and cobalamin bound states. Apo MTR adopts a conformation where the two halves of the enzyme act independently with the C-half posed to bind cobalamin. Binding of cobalamin and its activation causes conformational changes in MTR that result in a flexible catalytically active state. AlphaFold predictions, validated by interaction studies, show that MMADHC interacts with the C-half of apo MTR to facilitate cobalamin loading. Unexpectedly we found that MTRR interacts at two distinct sites within the C-half of MTR which may aid in activation. Collectively these findings lay the groundwork to uncover the mechanisms through how MMADHC and MTRR coordinate cobalamin loading and activation of human MTR.
History
DepositionSep 26, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 15, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Methionine synthase


Theoretical massNumber of molelcules
Total (without water)140,6961
Polymers140,6961
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Methionine synthase / MS / 5-methyltetrahydrofolate--homocysteine methyltransferase / Cobalamin-dependent methionine ...MS / 5-methyltetrahydrofolate--homocysteine methyltransferase / Cobalamin-dependent methionine synthase / Vitamin-B12 dependent methionine synthase


Mass: 140695.766 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MTR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q99707, methionine synthase
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human Methionine Synthase With Methylcobalamin, Activation Domain From Full-Length
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.14 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 65.2 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting
9ISOLDEmodel refinement
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 70000 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 67.24 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00342787
ELECTRON MICROSCOPYf_angle_d0.49223778
ELECTRON MICROSCOPYf_chiral_restr0.0412394
ELECTRON MICROSCOPYf_plane_restr0.0047493
ELECTRON MICROSCOPYf_dihedral_angle_d4.3266377

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