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- EMDB-55191: Human Methionine Synthase With Methyltetrahydrofolate, C-Half Fro... -

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Basic information

Entry
Database: EMDB / ID: EMD-55191
TitleHuman Methionine Synthase With Methyltetrahydrofolate, C-Half From Full-Length
Map data
Sample
  • Complex: Human Methionine Synthase With Methyltetrahydrofolate, C-Half From Full-Length
    • Protein or peptide: Methionine synthase
KeywordsMethionine / Folate / Cobalamin / TRANSFERASE
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.82 Å
AuthorsFerreira DSM / Yue WW / McCorvie TJ
Funding support United Kingdom, 1 items
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, 2025-
Header (metadata) releaseOct 15, 2025-
Map releaseOct 15, 2025-
UpdateMay 27, 2026-
Current statusMay 27, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_55191.png

Downloads & links

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Map

FileDownload / File: emd_55191.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesX (Sec.)Y (Row.)Z (Col.)
1.02 Å/pix.
x 200 pix.
= 203.2 Å		1.02 Å/pix.
x 200 pix.
= 203.2 Å		1.02 Å/pix.
x 200 pix.
= 203.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.016 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.13706133 - 0.3225046
Average (Standard dev.)0.00013263345 (±0.007820406)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 203.20001 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_55191_additional_1.map
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Half map: #2

Fileemd_55191_half_map_1.map
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Half map: #1

Fileemd_55191_half_map_2.map
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Sample components

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Entire : Human Methionine Synthase With Methyltetrahydrofolate, C-Half Fro...

EntireName: Human Methionine Synthase With Methyltetrahydrofolate, C-Half From Full-Length
Components
  • Complex: Human Methionine Synthase With Methyltetrahydrofolate, C-Half From Full-Length
    • Protein or peptide: Methionine synthase

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Supramolecule #1: Human Methionine Synthase With Methyltetrahydrofolate, C-Half Fro...

SupramoleculeName: Human Methionine Synthase With Methyltetrahydrofolate, C-Half From Full-Length
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 140 KDa

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Macromolecule #1: Methionine synthase

MacromoleculeName: Methionine synthase / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: methionine synthase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 140.695766 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSPALQDLSQ PEGLKKTLRD EINAILQKRI MVLDGGMGTM IQREKLNEEH FRGQEFKDHA RPLKGNNDIL SITQPDVIYQ IHKEYLLAG ADIIETNTFS STSIAQADYG LEHLAYRMNM CSAGVARKAA EEVTLQTGIK RFVAGALGPT NKTLSVSPSV E RPDYRNIT ...String:
MSPALQDLSQ PEGLKKTLRD EINAILQKRI MVLDGGMGTM IQREKLNEEH FRGQEFKDHA RPLKGNNDIL SITQPDVIYQ IHKEYLLAG ADIIETNTFS STSIAQADYG LEHLAYRMNM CSAGVARKAA EEVTLQTGIK RFVAGALGPT NKTLSVSPSV E RPDYRNIT FDELVEAYQE QAKGLLDGGV DILLIETIFD TANAKAALFA LQNLFEEKYA PRPIFISGTI VDKSGRTLSG QT GEGFVIS VSHGEPLCIG LNCALGAAEM RPFIEIIGKC TTAYVLCYPN AGLPNTFGDY DETPSMMAKH LKDFAMDGLV NIV GGCCGS TPDHIREIAE AVKNCKPRVP PATAFEGHML LSGLEPFRIG PYTNFVNIGE RCNVAGSRKF AKLIMAGNYE EALC VAKVQ VEMGAQVLDV NMDDGMLDGP SAMTRFCNLI ASEPDIAKVP LCIDSSNFAV IEAGLKCCQG KCIVNSISLK EGEDD FLEK ARKIKKYGAA MVVMAFDEEG QATETDTKIR VCTRAYHLLV KKLGFNPNDI IFDPNILTIG TGMEEHNLYA INFIHA TKV IKETLPGARI SGGLSNLSFS FRGMEAIREA MHGVFLYHAI KSGMDMGIVN AGNLPVYDDI HKELLQLCED LIWNKDP EA TEKLLRYAQT QGTGGKKVIQ TDEWRNGPVE ERLEYALVKG IEKHIIEDTE EARLNQKKYP RPLNIIEGPL MNGMKIVG D LFGAGKMFLP QVIKSARVMK KAVGHLIPFM EKEREETRVL NGTVEEEDPY QGTIVLATVK GDVHDIGKNI VGVVLGCNN FRVIDLGVMT PCDKILKAAL DHKADIIGLS GLITPSLDEM IFVAKEMERL AIRIPLLIGG ATTSKTHTAV KIAPRYSAPV IHVLDASKS VVVCSQLLDE NLKDEYFEEI MEEYEDIRQD HYESLKERRY LPLSQARKSG FQMDWLSEPH PVKPTFIGTQ V FEDYDLQK LVDYIDWKPF FDVWQLRGKY PNRGFPKIFN DKTVGGEARK VYDDAHNMLN TLISQKKLRA RGVVGFWPAQ SI QDDIHLY AEAAVPQAAE PIATFYGLRQ QAEKDSASTE PYYCLSDFIA PLHSGIRDYL GLFAVACFGV EELSKAYEDD GDD YSSIMV KALGDRLAEA FAEELHERVR RELWAYCGSE QLDVADLRRL RYKGIRPAPG YPSQPDHTEK LTMWRLADIE QSTG IRLTE SLAMAPASAV SGLYFSNLKS KYFAVGKISK DQVEDYALRK NISVAEVEKW LGPILGYDTD

UniProtKB: Methionine synthase

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 65.2 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.82 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 100343
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9ssq:
Human Methionine Synthase With Methyltetrahydrofolate, C-Half From Full-Length

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