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- EMDB-16975: MutSbeta bound to homoduplex plasmid DNA -

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Basic information

Entry
Database: EMDB / ID: EMD-16975
TitleMutSbeta bound to homoduplex plasmid DNA
Map dataMutSbeta bound to homoduplex plasmid DNA
Sample
  • Complex: MutSbeta bound to homoduplex plasmid DNA
KeywordsDNA repair protein complex / DNA BINDING PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 7.08 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
DepositionMar 31, 2023-
Header (metadata) releaseMay 24, 2023-
Map releaseMay 24, 2023-
UpdateMay 27, 2026-
Current statusMay 27, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16975.png

Downloads & links

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Map

FileDownload / File: emd_16975.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMutSbeta bound to homoduplex plasmid DNA
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.14 Å/pix.
x 256 pix.
= 292.608 Å		1.14 Å/pix.
x 256 pix.
= 292.608 Å		1.14 Å/pix.
x 256 pix.
= 292.608 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.143 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-1.1396093 - 3.2368493
Average (Standard dev.)-0.0005796332 (±0.087721944)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 292.608 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: MutSbeta bound to homoduplex plasmid DNA

Fileemd_16975_half_map_1.map
AnnotationMutSbeta bound to homoduplex plasmid DNA
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: MutSbeta bound to homoduplex plasmid DNA

Fileemd_16975_half_map_2.map
AnnotationMutSbeta bound to homoduplex plasmid DNA
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : MutSbeta bound to homoduplex plasmid DNA

EntireName: MutSbeta bound to homoduplex plasmid DNA
Components
  • Complex: MutSbeta bound to homoduplex plasmid DNA

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Supramolecule #1: MutSbeta bound to homoduplex plasmid DNA

SupramoleculeName: MutSbeta bound to homoduplex plasmid DNA / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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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: 7.5
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: 59.93 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / 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: PDB ENTRY
PDB model - PDB ID:

3thz

Final reconstructionResolution.type: BY AUTHOR / Resolution: 7.08 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 11791
Initial angle assignmentType: OTHER
Final angle assignmentType: MAXIMUM LIKELIHOOD

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