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- PDB-9sqq: Structure of trans-basal conformer of wild-type human CBS enzyme ... -

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Basic information

Entry
Database: PDB / ID: 9sqq
TitleStructure of trans-basal conformer of wild-type human CBS enzyme in absence of substrate and allosteric activators- by Helical approach
ComponentsCystathionine beta-synthase
KeywordsLYASE / transsulfuration pathway / L-serine hydro-lyase / heme-binding protein / CBS domain
Function / homology
Function and homology information


Cysteine formation from homocysteine / L-homocysteine catabolic process / modified amino acid binding / cystathionine beta-synthase / cystathionine beta-synthase activity / Metabolism of ingested SeMet, Sec, MeSec into H2Se / carbon monoxide binding / hydrogen sulfide biosynthetic process / L-serine catabolic process / homocysteine metabolic process ...Cysteine formation from homocysteine / L-homocysteine catabolic process / modified amino acid binding / cystathionine beta-synthase / cystathionine beta-synthase activity / Metabolism of ingested SeMet, Sec, MeSec into H2Se / carbon monoxide binding / hydrogen sulfide biosynthetic process / L-serine catabolic process / homocysteine metabolic process / L-cysteine catabolic process / L-cysteine biosynthetic process / L-serine metabolic process / transsulfuration / nitric oxide binding / DNA protection / S-adenosyl-L-methionine binding / nitrite reductase (NO-forming) activity / oxygen binding / response to nutrient levels / cellular response to insulin stimulus / pyridoxal phosphate binding / cellular response to hypoxia / ubiquitin protein ligase binding / heme binding / negative regulation of apoptotic process / enzyme binding / protein homodimerization activity / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Cystathionine beta-synthase, C-terminal domain / Cystathionine beta-synthase / Cysteine synthase/cystathionine beta-synthase, pyridoxal-phosphate attachment site / Cysteine synthase/cystathionine beta-synthase P-phosphate attachment site. / : / Pyridoxal-phosphate dependent enzyme / Pyridoxal-phosphate dependent enzyme / Tryptophan synthase beta subunit-like PLP-dependent enzyme / Domain in cystathionine beta-synthase and other proteins. / CBS domain superfamily ...Cystathionine beta-synthase, C-terminal domain / Cystathionine beta-synthase / Cysteine synthase/cystathionine beta-synthase, pyridoxal-phosphate attachment site / Cysteine synthase/cystathionine beta-synthase P-phosphate attachment site. / : / Pyridoxal-phosphate dependent enzyme / Pyridoxal-phosphate dependent enzyme / Tryptophan synthase beta subunit-like PLP-dependent enzyme / Domain in cystathionine beta-synthase and other proteins. / CBS domain superfamily / CBS domain / CBS domain / CBS domain profile.
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING FE / Cystathionine beta-synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3 Å
AuthorsInayathulla, M. / Tomas, M.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation10.001.133 Switzerland
CitationJournal: Nat Commun / Year: 2026
Title: Structural basis for a filamentous morpheein model of human cystathionine beta-synthase.
Authors: Inayathulla Mohammed / Ela Mijatovic / Thilo Magnus Philipp / Lucia Janickova / Kelly Ascencao / Francisco J Asturias / Luis Alfonso Martinez-Cruz / Csaba Szabo / Henning Stahlberg / Tomas Majtan /
Abstract: Human cystathionine beta-synthase (CBS) is a vital enzyme that regulates sulfur amino acid metabolism, hydrogen sulfide production, and cellular redox balance. Using a multidisciplinary approach, we ...Human cystathionine beta-synthase (CBS) is a vital enzyme that regulates sulfur amino acid metabolism, hydrogen sulfide production, and cellular redox balance. Using a multidisciplinary approach, we demonstrate that CBS functions as a filamentous morpheein, with its stability, turnover, and activity governed by dynamic quaternary structural transitions. Three distinct filamentous assemblies were resolved by cryo-EM and are mediated by the oligomerization loop (residues 516-525): (i) ligand-free trans-dimers that form trans-basal filaments with basal stability and activity, (ii) adenosylornithine-bound cis-dimers that assemble into stabilized cis-basal filaments and (iii) S-adenosylmethionine-bound allo-dimers, which, together with cis-dimers, form highly stable, allo-activated stacked filaments. These reversible filamentous assemblies redefine CBS biology by integrating oligomerization and allosteric regulation within a morpheein framework. These findings provide a transformative perspective on CBS function and open avenues for pharmacological targeting of dysregulated CBS in various diseases including homocystinuria, cancer, and Down syndrome.
History
DepositionSep 23, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 29, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cystathionine beta-synthase
B: Cystathionine beta-synthase
E: Cystathionine beta-synthase
F: Cystathionine beta-synthase
C: Cystathionine beta-synthase
D: Cystathionine beta-synthase
G: Cystathionine beta-synthase
H: Cystathionine beta-synthase
I: Cystathionine beta-synthase
J: Cystathionine beta-synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)569,07020
Polymers562,90510
Non-polymers6,16510
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
d_1ens_1chain "J"
d_2ens_1chain "B"
d_3ens_1chain "C"
d_4ens_1chain "D"
d_5ens_1chain "E"
d_6ens_1chain "F"
d_7ens_1chain "G"
d_8ens_1chain "H"
d_9ens_1chain "I"
d_10ens_1chain "A"

NCS domain segments:

Ens-ID: ens_1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11LEULEUARGARGJJ42 - 5481 - 507
d_12HEMHEMHEMHEMJT601
d_21LEULEUARGARGBB42 - 5481 - 507
d_22HEMHEMHEMHEMBL601
d_31LEULEUARGARGCE42 - 5481 - 507
d_32HEMHEMHEMHEMCO601
d_41LEULEUARGARGDF42 - 5481 - 507
d_42HEMHEMHEMHEMDP601
d_51LEULEUARGARGEC42 - 5481 - 507
d_52HEMHEMHEMHEMEM601
d_61LEULEUARGARGFD42 - 5481 - 507
d_62HEMHEMHEMHEMFN601
d_71LEULEUARGARGGG42 - 5481 - 507
d_72HEMHEMHEMHEMGQ601
d_81LEULEUARGARGHH42 - 5481 - 507
d_82HEMHEMHEMHEMHR601
d_91LEULEUARGARGII42 - 5481 - 507
d_92HEMHEMHEMHEMIS601
d_101LEULEUARGARGAA42 - 5481 - 507
d_102HEMHEMHEMHEMAK601

NCS oper:
IDCodeMatrixVector
1given(0.389437068252, 0.921001069924, 0.00978769993339), (0.921046515431, -0.389452415406, -0.00036407122093), (0.00347653339632, 0.00915670974664, -0.999952033041)-60.0590116124, 88.3395245238, 416.768385783
2given(-0.978102816672, 0.208120268303, 0.000913202591152), (0.208120692162, 0.978103072781, 0.000395614116614), (-0.000810870944383, 0.00057700763713, -0.999999504775)326.068305483, -34.4158145877, 218.330470116
3given(-0.419912407805, -0.907564572772, -0.00034061670236), (0.907564442274, -0.419912533937, 0.000496952892726), (-0.000594046062364, -0.000100454921756, 0.999999818509)429.404757705, 95.2787136781, -50.1368763667
4given(-0.56169279232, -0.827224510744, -0.0141709519922), (0.827337358527, -0.561682351946, -0.00508239103039), (-0.00375529521075, -0.0145789003985, 0.999886670289)443.591425051, 138.926658456, 103.117107561
5given(-0.999092266994, 0.0413995116752, 0.0100360583223), (0.041441080338, 0.999133062642, 0.0039698862231), (-0.00986300633738, 0.00438218772555, -0.999941757072)360.2352007, -6.46058531535, 369.236906827
6given(0.453943606171, -0.891028408907, 0.00189127944361), (-0.891028720784, -0.453945860436, -0.000987183176465), (0.00173814672938, -0.00123705881221, -0.999997724263)265.435454857, 432.1216698, 318.572996264
7given(-0.439450676611, 0.898266636903, 0.000389683338099), (-0.898265858448, -0.43945081441, 0.00119551678848), (0.00124513950523, 0.000175331423375, 0.999999209443)99.6318037685, 430.699911699, 49.8853525767
8given(0.615111256815, 0.78844030143, -0.000181164156543), (0.788440307361, -0.615111184322, 0.000335634794715), (0.000153191899827, -0.000349289863676, -0.999999927264)-74.3825544542, 152.38289352, 268.442542262
9given(0.968334526986, -0.249471301964, -0.00960798330184), (0.249483639816, 0.968379009291, 8.84795002719E-5), (0.00928209625499, -0.00248271240048, 0.999953838349)52.0219163686, -38.7710643476, 149.518581965

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Components

#1: Protein
Cystathionine beta-synthase / Beta-thionase / Serine sulfhydrase


Mass: 56290.477 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CBS / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P35520, cystathionine beta-synthase
#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C34H32FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: oligomeric assembly of human CBS enzyme / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
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 defocus max: 2400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.5particle selection
2EPUimage acquisition
12cryoSPARC4.53D reconstruction
13PHENIXdev_5430model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -116.06 ° / Axial rise/subunit: 49.97 Å / Axial symmetry: D1
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 335525 / Algorithm: FOURIER SPACE / Symmetry type: HELICAL
Atomic model buildingProtocol: FLEXIBLE FIT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 56.67 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003840710
ELECTRON MICROSCOPYf_angle_d0.694155290
ELECTRON MICROSCOPYf_chiral_restr0.04426200
ELECTRON MICROSCOPYf_plane_restr0.00497070
ELECTRON MICROSCOPYf_dihedral_angle_d8.62815560
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2JJELECTRON MICROSCOPYNCS constraints7.78825260116E-13
ens_1d_3JJELECTRON MICROSCOPYNCS constraints1.45056593362E-12
ens_1d_4JJELECTRON MICROSCOPYNCS constraints2.8797026955E-12
ens_1d_5JJELECTRON MICROSCOPYNCS constraints3.15265128755E-12
ens_1d_6JJELECTRON MICROSCOPYNCS constraints4.09150120262E-13
ens_1d_7JJELECTRON MICROSCOPYNCS constraints5.85307481884E-13
ens_1d_8JJELECTRON MICROSCOPYNCS constraints7.34502731198E-13
ens_1d_9JJELECTRON MICROSCOPYNCS constraints6.24221930085E-13
ens_1d_10JJELECTRON MICROSCOPYNCS constraints1.34127555352E-12

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