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- PDB-8olx: MutSbeta bound to (CAG)2 DNA (canonical form) -

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Basic information

Entry
Database: PDB / ID: 8olx
TitleMutSbeta bound to (CAG)2 DNA (canonical form)
Components
  • (DNA mismatch repair protein ...) x 2
  • DNA (21-MER)
  • DNA (27-MER)
KeywordsDNA BINDING PROTEIN / PROTEROS BIOSTRUCTURES GMBH
Function / homology
Function and homology information


somatic recombination of immunoglobulin genes involved in immune response / MutSbeta complex / Defective Mismatch Repair Associated With MSH3 / MutSalpha complex / Defective Mismatch Repair Associated With MSH2 / Defective Mismatch Repair Associated With MSH6 / guanine/thymine mispair binding / somatic recombination of immunoglobulin gene segments / B cell mediated immunity / maintenance of DNA repeat elements ...somatic recombination of immunoglobulin genes involved in immune response / MutSbeta complex / Defective Mismatch Repair Associated With MSH3 / MutSalpha complex / Defective Mismatch Repair Associated With MSH2 / Defective Mismatch Repair Associated With MSH6 / guanine/thymine mispair binding / somatic recombination of immunoglobulin gene segments / B cell mediated immunity / maintenance of DNA repeat elements / positive regulation of isotype switching to IgA isotypes / centromeric DNA binding / positive regulation of isotype switching to IgG isotypes / mismatched DNA binding / mitotic recombination / negative regulation of DNA recombination / isotype switching / Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) / Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) / DNA damage tolerance / response to UV-B / oxidative phosphorylation / mitotic intra-S DNA damage checkpoint signaling / ATP-dependent DNA damage sensor activity / germ cell development / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / response to X-ray / ATP-dependent activity, acting on DNA / mismatch repair / somatic hypermutation of immunoglobulin genes / B cell differentiation / determination of adult lifespan / TP53 Regulates Transcription of DNA Repair Genes / male gonad development / enzyme activator activity / double-strand break repair / double-stranded DNA binding / in utero embryonic development / damaged DNA binding / negative regulation of neuron apoptotic process / chromosome, telomeric region / DNA repair / chromatin binding / enzyme binding / protein homodimerization activity / ATP hydrolysis activity / DNA binding / nucleoplasm / ATP binding / membrane / nucleus
Similarity search - Function
MutS, connector domain / DNA repair protein MutS, domain I / DNA mismatch repair Msh2-type / DNA mismatch repair protein Msh2 / DNA mismatch repair protein MutS-like, N-terminal / DNA mismatch repair protein MutS, connector domain / DNA mismatch repair protein MutS, clamp / DNA mismatch repair protein MutS, N-terminal / MutS, connector domain superfamily / MutS domain I ...MutS, connector domain / DNA repair protein MutS, domain I / DNA mismatch repair Msh2-type / DNA mismatch repair protein Msh2 / DNA mismatch repair protein MutS-like, N-terminal / DNA mismatch repair protein MutS, connector domain / DNA mismatch repair protein MutS, clamp / DNA mismatch repair protein MutS, N-terminal / MutS, connector domain superfamily / MutS domain I / MutS domain II / MutS family domain IV / MutS domain III / DNA mismatch repair MutS family / DNA mismatch repair protein MutS, C-terminal / DNA mismatch repair protein MutS, core / DNA mismatch repair protein MutS, core domain superfamily / MutS domain V / DNA mismatch repair proteins mutS family signature. / DNA-binding domain of DNA mismatch repair MUTS family / ATPase domain of DNA mismatch repair MUTS family / MutS, DNA mismatch repair protein, domain I / Nucleotidyltransferase; domain 5 / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / DNA / DNA (> 10) / DNA mismatch repair protein Msh3 / DNA mismatch repair protein Msh2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsLee, J.-H. / Thomsen, M. / Daub, H. / Steinbacher, S. / Sztyler, A. / Thieulin-Pardo, G. / Neudegger, T. / Plotnikov, N. / Iyer, R.R. / Wilkinson, H. ...Lee, J.-H. / Thomsen, M. / Daub, H. / Steinbacher, S. / Sztyler, A. / Thieulin-Pardo, G. / Neudegger, T. / Plotnikov, N. / Iyer, R.R. / Wilkinson, H. / Monteagudo, E. / Felsenfeld, D.P. / Haque, T. / Finley, M. / Dominguez, C. / Vogt, T.F. / Prasad, B.C.
Funding support United States, 1items
OrganizationGrant numberCountry
CHDI Foundation United States
Citation
Journal: Nucleic Acids Res / Year: 2025
Title: Elucidation of multiple high-resolution states of human MutSβ by cryo-EM reveals interplay between ATP/ADP binding and heteroduplex DNA recognition.
Authors: Jung-Hoon Lee / Maren Thomsen / Herwin Daub / Gabriel Thieulin-Pardo / Stefan Steinbacher / Agnieszka Sztyler / Vinay Dahiya / Tobias Neudegger / Celia Dominguez / Ravi R Iyer / Hilary A ...Authors: Jung-Hoon Lee / Maren Thomsen / Herwin Daub / Gabriel Thieulin-Pardo / Stefan Steinbacher / Agnieszka Sztyler / Vinay Dahiya / Tobias Neudegger / Celia Dominguez / Ravi R Iyer / Hilary A Wilkinson / Edith Monteagudo / Nikolay V Plotnikov / Dan P Felsenfeld / Tasir S Haque / Michael Finley / Julien Boudet / Thomas F Vogt / Brinda C Prasad /
Abstract: Human and mouse genetic studies have demonstrated a role for DNA mismatch repair (MMR) molecular machines in modulating the rate of somatic expansion of the huntingtin (HTT) CAG repeats, and onset ...Human and mouse genetic studies have demonstrated a role for DNA mismatch repair (MMR) molecular machines in modulating the rate of somatic expansion of the huntingtin (HTT) CAG repeats, and onset and progression of Huntington's Disease (HD). MutSβ, a key component of the MMR pathway, is a heterodimeric protein of MSH2 and MSH3 that recognizes and initiates the repair of extrahelical DNA extrusions. Loss-of-function of mouse Msh3 and reduced-expression alleles of human MSH3 lead to slower rates of somatic expansion and delayed disease onset in humans, signifying MSH3 as a promising therapeutic target for HD. Here we report biochemical and cryo-electron microscopy analyses of human MutSβ, demonstrating MutSβ undergoes conformational changes induced by nucleotide and DNA binding. We present multiple conformations of MutSβ including the DNA-free MutSβ compatible with precisely complementary base-paired homoduplex DNA binding, two distinct structures of MutSβ bound to (CAG)2 DNA, a sliding clamp form and a DNA-unbound, ATP-bound conformation. Along with evidence for novel conformational states adopted by MutSβ to initiate the MMR cascade, these structures provide a foundation for structure-guided drug discovery.
#1: Journal: Biorxiv / Year: 2024
Title: Elucidation of multiple high-resolution states of human MutS beta by cryo-EM reveals interplay between ATP/ADP binding and heteroduplex DNA recognition
Authors: Lee, J.H. / Thomsen, M. / Daub, H. / Thieulin-Pardo, G. / Steinbacher, S.C. / Sztyler, A. / Dahiya, V. / Neudegger, T. / Dominguez, C. / Iyer, R.R. / Wilkinson, H.A. / Monteagudo, E. / ...Authors: Lee, J.H. / Thomsen, M. / Daub, H. / Thieulin-Pardo, G. / Steinbacher, S.C. / Sztyler, A. / Dahiya, V. / Neudegger, T. / Dominguez, C. / Iyer, R.R. / Wilkinson, H.A. / Monteagudo, E. / Plotnikov, N.V. / Felsenfeld, D.P. / Haque, T.S. / Finley, M. / Boudet, J. / Vogt, T.F. / Prasad, B.C.
History
DepositionMar 30, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 24, 2023Provider: repository / Type: Initial release
Revision 1.0May 24, 2023Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.1Jul 24, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update
Revision 2.0Nov 13, 2024Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Non-polymer description / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / em_admin / entity / entity_poly / entity_poly_seq / ndb_struct_na_base_pair / ndb_struct_na_base_pair_step / pdbx_entity_src_syn / pdbx_entry_details / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / pdbx_validate_rmsd_bond / struct_conn
Item: _atom_site.auth_comp_id / _atom_site.label_comp_id ..._atom_site.auth_comp_id / _atom_site.label_comp_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _em_admin.last_update / _entity.formula_weight / _entity.pdbx_description / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.type / _entity_poly_seq.mon_id / _ndb_struct_na_base_pair.i_label_comp_id / _ndb_struct_na_base_pair.pair_name / _ndb_struct_na_base_pair_step.i_label_comp_id_1 / _ndb_struct_na_base_pair_step.i_label_comp_id_2 / _ndb_struct_na_base_pair_step.step_name / _pdbx_entity_src_syn.ncbi_taxonomy_id / _pdbx_entity_src_syn.organism_scientific / _pdbx_entry_details.has_protein_modification / _pdbx_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.mon_id / _pdbx_poly_seq_scheme.pdb_mon_id / _pdbx_unobs_or_zero_occ_residues.auth_comp_id / _pdbx_unobs_or_zero_occ_residues.label_comp_id / _pdbx_validate_rmsd_bond.auth_comp_id_1 / _pdbx_validate_rmsd_bond.auth_comp_id_2 / _pdbx_validate_rmsd_bond.bond_deviation / _pdbx_validate_rmsd_bond.bond_target_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_label_comp_id
Revision 2.1Dec 4, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 2.2May 27, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update
Revision 1.1May 27, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin / Data content type: EM metadata / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DNA mismatch repair protein Msh2
B: DNA mismatch repair protein Msh3
C: DNA (21-MER)
D: DNA (27-MER)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)247,6836
Polymers247,2314
Non-polymers4522
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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DNA mismatch repair protein ... , 2 types, 2 molecules AB

#1: Protein DNA mismatch repair protein Msh2 / hMSH2 / MutS protein homolog 2


Mass: 104861.875 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MSH2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P43246
#2: Protein DNA mismatch repair protein Msh3 / hMSH3 / Divergent upstream protein / DUP / Mismatch repair protein 1 / MRP1


Mass: 127618.703 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MSH3, DUC1, DUG / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P20585

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DNA chain , 2 types, 2 molecules CD

#3: DNA chain DNA (21-MER)


Mass: 6399.135 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: DNA chain DNA (27-MER)


Mass: 8351.386 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM

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Details

Has ligand of interestY
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: MutSbeta bound to (CAG)2 DNA (canonical form) / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 55.95 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0267 / Classification: refinement
EM software
IDNameCategory
2EPUimage acquisition
13cryoSPARCmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 379788 / Symmetry type: POINT
RefinementResolution: 3.1→292.54 Å / Cor.coef. Fo:Fc: 0.855 / SU B: 7.136 / SU ML: 0.12 / ESU R: 0.106
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
RfactorNum. reflection% reflection
Rwork0.37151 --
obs0.37151 1759634 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 109.228 Å2
Baniso -1Baniso -2Baniso -3
1-5.84 Å22.36 Å2-0.19 Å2
2---1.9 Å20.01 Å2
3----3.94 Å2
Refinement stepCycle: 1 / Total: 14475
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0040.01214811
ELECTRON MICROSCOPYr_bond_other_d
ELECTRON MICROSCOPYr_angle_refined_deg0.9941.59720165
ELECTRON MICROSCOPYr_angle_other_deg
ELECTRON MICROSCOPYr_dihedral_angle_1_deg4.93351688
ELECTRON MICROSCOPYr_dihedral_angle_2_deg35.86823.102706
ELECTRON MICROSCOPYr_dihedral_angle_3_deg19.55152591
ELECTRON MICROSCOPYr_dihedral_angle_4_deg19.0491577
ELECTRON MICROSCOPYr_chiral_restr0.0790.21966
ELECTRON MICROSCOPYr_gen_planes_refined0.0040.0210609
ELECTRON MICROSCOPYr_gen_planes_other
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it5.0269.0396785
ELECTRON MICROSCOPYr_mcbond_other
ELECTRON MICROSCOPYr_mcangle_it8.86613.5468459
ELECTRON MICROSCOPYr_mcangle_other
ELECTRON MICROSCOPYr_scbond_it5.61312.5058026
ELECTRON MICROSCOPYr_scbond_other
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other
ELECTRON MICROSCOPYr_long_range_B_refined25.23661866
ELECTRON MICROSCOPYr_long_range_B_other
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.1→3.181 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.519 130287 -
obs--100 %

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