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TitleElucidation of multiple high-resolution states of human MutSβ by cryo-EM reveals interplay between ATP/ADP binding and heteroduplex DNA recognition.
Journal, issue, pagesNucleic Acids Res, Vol. 53, Issue 12, Year 2025
Publish dateJun 20, 2025
AuthorsJung-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 /
PubMed AbstractHuman 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.
External linksNucleic Acids Res / PubMed:40613711 / PubMed Central
MethodsEM (single particle)
Resolution3.02 - 7.08 Å
Structure data

16964

8olx

EMDB-16964, PDB-8olx:
MutSbeta bound to (CAG)2 DNA (canonical form)
Method: EM (single particle) / Resolution: 3.1 Å

16969

8om5

EMDB-16969, PDB-8om5:
DNA-free open form of MutSbeta
Method: EM (single particle) / Resolution: 3.52 Å

16971

8om9

EMDB-16971, PDB-8om9:
MutSbeta bound to (CAG)2 DNA (open form)
Method: EM (single particle) / Resolution: 3.32 Å

16972

8oma

EMDB-16972, PDB-8oma:
MutSbeta bound to 61bp homoduplex DNA
Method: EM (single particle) / Resolution: 3.29 Å

16973

8omo

EMDB-16973, PDB-8omo:
DNA-unbound MutSbeta-ATP complex (bent clamp form)
Method: EM (single particle) / Resolution: 3.43 Å

16974

8omq

EMDB-16974, PDB-8omq:
DNA-unbound MutSbeta-ATP complex (straight clamp form)
Method: EM (single particle) / Resolution: 3.11 Å

EMDB-16975: MutSbeta bound to homoduplex plasmid DNA
Method: EM (single particle) / Resolution: 7.08 Å

19605

8rz7

EMDB-19605, PDB-8rz7:
(CAG)2 DNA-bound MutSbeta in open form with kinked MSH2 clamp
Method: EM (single particle) / Resolution: 3.37 Å

19606

8rz8

EMDB-19606, PDB-8rz8:
MutSbeta-ATPgS with straight MSH2 clamp
Method: EM (single particle) / Resolution: 3.06 Å

19607

8rz9

EMDB-19607, PDB-8rz9:
MutSbeta-ATPgS with kinked MSH2 clamp
Method: EM (single particle) / Resolution: 3.02 Å

Chemicals

ChemComp-MG:
Unknown entry

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

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsDNA BINDING PROTEIN / PROTEROS BIOSTRUCTURES GMBH / Protein-DNA complex / DNA repair protein complex / DNA REPAIR / MISMATCH RECOGNITION / ABC FAMILY ATPASE

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