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- EMDB-19605: (CAG)2 DNA-bound MutSbeta in open form with kinked MSH2 clamp -

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Open data


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Basic information

Entry
Database: EMDB / ID: EMD-19605
Title(CAG)2 DNA-bound MutSbeta in open form with kinked MSH2 clamp
Map data
Sample
  • Complex: MutSbeta-DNA-ADP complex
    • Complex: DNA mismatch repair protein
      • Protein or peptide: DNA mismatch repair protein Msh2
      • Protein or peptide: DNA mismatch repair protein Msh3
    • Complex: Double stranded DNA
      • DNA: DNA_1
      • DNA: DNA_2
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION
KeywordsDNA REPAIR / MISMATCH RECOGNITION / ABC FAMILY ATPASE / DNA BINDING PROTEIN
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
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 ...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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
DNA mismatch repair protein Msh3 / DNA mismatch repair protein Msh2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.37 Å
AuthorsLee J-H / Thomsen M / Daub H / Steinbacher S / Sztyler A / Thieulin-Pardo G / Neudegger T / Plotnikov N / Iyer RR / Wilkinson H ...Lee J-H / Thomsen M / Daub H / Steinbacher S / Sztyler A / Thieulin-Pardo G / Neudegger T / Plotnikov N / Iyer RR / Wilkinson H / Monteagudo E / Felsenfeld DP / Haque T / Finley M / Dominguez C / Vogt TF / Prasad BC
Funding support United States, 1 items
OrganizationGrant numberCountry
CHDI Foundation United States
CitationJournal: 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.
History
DepositionFeb 12, 2024-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateMay 27, 2026-
Current statusMay 27, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19605.png

Downloads & links

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Map

FileDownload / File: emd_19605.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.91 Å/pix.
x 320 pix.
= 292.544 Å		0.91 Å/pix.
x 320 pix.
= 292.544 Å		0.91 Å/pix.
x 320 pix.
= 292.544 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.9142 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015
Minimum - Maximum-0.0017142801 - 1.9915048
Average (Standard dev.)0.0010726008 (±0.024038535)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 292.544 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_19605_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_19605_half_map_2.map
Projections & Slices
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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : MutSbeta-DNA-ADP complex

EntireName: MutSbeta-DNA-ADP complex
Components
  • Complex: MutSbeta-DNA-ADP complex
    • Complex: DNA mismatch repair protein
      • Protein or peptide: DNA mismatch repair protein Msh2
      • Protein or peptide: DNA mismatch repair protein Msh3
    • Complex: Double stranded DNA
      • DNA: DNA_1
      • DNA: DNA_2
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION

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Supramolecule #1: MutSbeta-DNA-ADP complex

SupramoleculeName: MutSbeta-DNA-ADP complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4

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Supramolecule #2: DNA mismatch repair protein

SupramoleculeName: DNA mismatch repair protein / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Double stranded DNA

SupramoleculeName: Double stranded DNA / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: DNA mismatch repair protein Msh2

MacromoleculeName: DNA mismatch repair protein Msh2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 104.861875 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAVQPKETLQ LESAAEVGFV RFFQGMPEKP TTTVRLFDRG DFYTAHGEDA LLAAREVFKT QGVIKYMGPA GAKNLQSVVL SKMNFESFV KDLLLVRQYR VEVYKNRAGN KASKENDWYL AYKASPGNLS QFEDILFGNN DMSASIGVVG VKMSAVDGQR Q VGVGYVDS ...String:
MAVQPKETLQ LESAAEVGFV RFFQGMPEKP TTTVRLFDRG DFYTAHGEDA LLAAREVFKT QGVIKYMGPA GAKNLQSVVL SKMNFESFV KDLLLVRQYR VEVYKNRAGN KASKENDWYL AYKASPGNLS QFEDILFGNN DMSASIGVVG VKMSAVDGQR Q VGVGYVDS IQRKLGLCEF PDNDQFSNLE ALLIQIGPKE CVLPGGETAG DMGKLRQIIQ RGGILITERK KADFSTKDIY QD LNRLLKG KKGEQMNSAV LPEMENQVAV SSLSAVIKFL ELLSDDSNFG QFELTTFDFS QYMKLDIAAV RALNLFQGSV EDT TGSQSL AALLNKCKTP QGQRLVNQWI KQPLMDKNRI EERLNLVEAF VEDAELRQTL QEDLLRRFPD LNRLAKKFQR QAAN LQDCY RLYQGINQLP NVIQALEKHE GKHQKLLLAV FVTPLTDLRS DFSKFQEMIE TTLDMDQVEN HEFLVKPSFD PNLSE LREI MNDLEKKMQS TLISAARDLG LDPGKQIKLD SSAQFGYYFR VTCKEEKVLR NNKNFSTVDI QKNGVKFTNS KLTSLN EEY TKNKTEYEEA QDAIVKEIVN ISSGYVEPMQ TLNDVLAQLD AVVSFAHVSN GAPVPYVRPA ILEKGQGRII LKASRHA CV EVQDEIAFIP NDVYFEKDKQ MFHIITGPNM GGKSTYIRQT GVIVLMAQIG CFVPCESAEV SIVDCILARV GAGDSQLK G VSTFMAEMLE TASILRSATK DSLIIIDELG RGTSTYDGFG LAWAISEYIA TKIGAFCMFA THFHELTALA NQIPTVNNL HVTALTTEET LTMLYQVKKG VCDQSFGIHV AELANFPKHV IECAKQKALE LEEFQYIGES QGYDIMEPAA KKCYLEREQG EKIIQEFLS KVKQMPFTEM SEENITIKLK QLKAEVIAKN NSFVNEIISR IKVTT

UniProtKB: DNA mismatch repair protein Msh2

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Macromolecule #2: DNA mismatch repair protein Msh3

MacromoleculeName: DNA mismatch repair protein Msh3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127.589641 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSRRKPASGG LAASSSAPAR QAVLSRFFQS TGSLKSTSSS TGAADQVDPG AAAAAAAAAA AAPPAPPAPA FPPQLPPHIA TEIDRRKKR PLENDGPVKK KVKKVQQKEG GSDLGMSGNS EPKKCLRTRN VSKSLEKLKE FCCDSALPQS RVQTESLQER F AVLPKCTD ...String:
MSRRKPASGG LAASSSAPAR QAVLSRFFQS TGSLKSTSSS TGAADQVDPG AAAAAAAAAA AAPPAPPAPA FPPQLPPHIA TEIDRRKKR PLENDGPVKK KVKKVQQKEG GSDLGMSGNS EPKKCLRTRN VSKSLEKLKE FCCDSALPQS RVQTESLQER F AVLPKCTD FDDISLLHAK NAVSSEDSKR QINQKDTTLF DLSQFGSSNT SHENLQKTAS KSANKRSKSI YTPLELQYIE MK QQHKDAV LCVECGYKYR FFGEDAEIAA RELNIYCHLD HNFMTASIPT HRLFVHVRRL VAKGYKVGVV KQTETAALKA IGD NRSSLF SRKLTALYTK STLIGEDVNP LIKLDDAVNV DEIMTDTSTS YLLCISENKE NVRDKKKGNI FIGIVGVQPA TGEV VFDSF QDSASRSELE TRMSSLQPVE LLLPSALSEQ TEALIHRATS VSVQDDRIRV ERMDNIYFEY SHAFQAVTEF YAKDT VDIK GSQIISGIVN LEKPVICSLA AIIKYLKEFN LEKMLSKPEN FKQLSSKMEF MTINGTTLRN LEILQNQTDM KTKGSL LWV LDHTKTSFGR RKLKKWVTQP LLKLREINAR LDAVSEVLHS ESSVFGQIEN HLRKLPDIER GLCSIYHKKC STQEFFL IV KTLYHLKSEF QAIIPAVNSH IQSDLLRTVI LEIPELLSPV EHYLKILNEQ AAKVGDKTEL FKDLSDFPLI KKRKDEIQ G VIDEIRMHLQ EIRKILKNPS AQYVTVSGQE FMIEIKNSAV SCIPTDWVKV GSTKAVSRFH SPFIVENYRH LNQLREQLV LDCSAEWLDF LEKFSEHYHS LCKAVHHLAT VDCIFSLAKV AKQGDYCRPT VQEERKIVIK NGRHPVIDVL LGEQDQYVPN NTDLSEDSE RVMIITGPNM GGKSSYIKQV ALITIMAQIG SYVPAEEATI GIVDGIFTRM GAADNIYKGQ STFMEELTDT A EIIRKATS QSLVILDELG RGTSTHDGIA IAYATLEYFI RDVKSLTLFV THYPPVCELE KNYSHQVGNY HMGFLVSEDE SK LDPGAAE QVPDFVTFLY QITRGIAARS YGLNVAKLAD VPGEILKKAA HKSKELEGLI NTKRKRLKYF AKLWTMHNAQ DLQ KWTEEF NMEETQTSLL H

UniProtKB: DNA mismatch repair protein Msh3

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Macromolecule #3: DNA_1

MacromoleculeName: DNA_1 / type: dna / ID: 3 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.355037 KDa
SequenceString: (DC)(DT)(DG)(DA)(DA)(DG)(DC)(DT)(DT)(DA) (DG)(DC)(DT)(DT)(DA)(DG)(DG)(DA)(DT)(DC) (DA)(DT)(DC)(DG)(DA)(DG)(DG)(DA)(DT) (DC)(DC)(DA)(DG)(DC)(DA)(DG)(DA)(DG)(DC) (DT) (DC)(DG)(DG)(DT)(DG)(DC) ...String:
(DC)(DT)(DG)(DA)(DA)(DG)(DC)(DT)(DT)(DA) (DG)(DC)(DT)(DT)(DA)(DG)(DG)(DA)(DT)(DC) (DA)(DT)(DC)(DG)(DA)(DG)(DG)(DA)(DT) (DC)(DC)(DA)(DG)(DC)(DA)(DG)(DA)(DG)(DC) (DT) (DC)(DG)(DG)(DT)(DG)(DC)(DA)(DA) (DT)(DT)(DC)(DA)(DG)(DC)(DG)(DG)(DT)(DA) (DC)(DC) (DC)(DA)(DA)(DT)(DT)(DC)

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Macromolecule #4: DNA_2

MacromoleculeName: DNA_2 / type: dna / ID: 4 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.49185 KDa
SequenceString: (DG)(DA)(DA)(DT)(DT)(DG)(DG)(DG)(DT)(DA) (DC)(DC)(DG)(DC)(DT)(DG)(DA)(DA)(DT)(DT) (DG)(DC)(DA)(DC)(DC)(DG)(DA)(DG)(DC) (DT)(DG)(DA)(DT)(DC)(DC)(DT)(DC)(DG)(DA) (DT) (DG)(DA)(DT)(DC)(DC)(DT) ...String:
(DG)(DA)(DA)(DT)(DT)(DG)(DG)(DG)(DT)(DA) (DC)(DC)(DG)(DC)(DT)(DG)(DA)(DA)(DT)(DT) (DG)(DC)(DA)(DC)(DC)(DG)(DA)(DG)(DC) (DT)(DG)(DA)(DT)(DC)(DC)(DT)(DC)(DG)(DA) (DT) (DG)(DA)(DT)(DC)(DC)(DT)(DA)(DA) (DG)(DC)(DT)(DA)(DA)(DG)(DC)(DT)(DT)(DC) (DA)(DG)

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Macromolecule #5: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 5 / Number of copies: 2 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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Macromolecule #6: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 6 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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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-PROPANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 49.35 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.7000000000000001 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.37 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 265375
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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