The crystal structure of human XPG, the xeroderma pigmentosum group G endonuclease, provides insight into nucleotide excision DNA repair
| Autor: | Carlos Fernández-Tornero, Rocío González-Corrochano, Srdja Drakulic, Nicholas M.I. Taylor, Sonia Huecas, Mercedes Spínola-Amilibia, Federico M. Ruiz |
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| Přispěvatelé: | Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), PharmaMar, CSIC - Unidad de Recursos de Información Científica para la Investigación (URICI), Ruiz, Federico M. [0000-0002-0385-7777], Taylor, Nicholas M. I. [0000-0003-0761-4921], Huecas, Sonia [0000-0002-6419-441X], Drakulic, Srdja [0000-0003-1622-1281, Fernández-Tornero, Carlos [0000-0001-5097-731X], Ruiz, Federico M., Taylor, Nicholas M. I., Huecas, Sonia, Drakulic, Srdja, Fernández-Tornero, Carlos |
| Rok vydání: | 2020 |
| Předmět: |
Protein Conformation
alpha-Helical Xeroderma pigmentosum DNA Repair DNA repair AcademicSubjects/SCI00010 Crystallography X-Ray Cockayne syndrome 03 medical and health sciences chemistry.chemical_compound Endonuclease 0302 clinical medicine Structural Biology Genetics medicine Humans Flap endonuclease 030304 developmental biology 0303 health sciences Nuclease Binding Sites biology Nuclear Proteins DNA medicine.disease Endonucleases DNA-Binding Proteins Molecular Docking Simulation chemistry 030220 oncology & carcinogenesis biology.protein Nucleotide excision repair Protein Binding Transcription Factors |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname 'Nucleic Acids Research ', vol: 48, pages: 9943-9958 (2020) Nucleic Acids Research |
| ISSN: | 0305-1048 |
| Popis: | 16 p.-7 fig.-1 tab. Nucleotide excision repair (NER) is an essential pathway to remove bulky lesions affecting one strand of DNA. Defects in components of this repair system are at the ground of genetic diseases such as xeroderma pigmentosum (XP) and Cockayne syndrome (CS). The XP complementation group G (XPG) endonuclease cleaves the damaged DNA strand on the 3' side of the lesion coordinated with DNA re-synthesis. Here, we determined crystal structures of the XPG nuclease domain in the absence and presence of DNA. The overall fold exhibits similarities to other flap endonucleases but XPG harbors a dynamic helical arch that is uniquely oriented and defines a gateway. DNA binding through a helix-2-turn-helix motif, assisted by one flanking alpha-helix on each side, shows high plasticity, which is likely relevant for DNA scanning. A positively-charged canyon defined by the hydrophobic wedge and beta-pin motifs provides an additional DNA-binding surface. Mutational analysis identifies helical arch residues that play critical roles in XPG function. A model for XPG participation in NER is proposed. Our structures and biochemical data represent a valuable tool to understand the atomic ground of XP and CS, and constitute a starting point for potential therapeutic applications. Spanish Ministry of Science [BFU2017-87397-P,BFU2013-48374-P to C.F.T.]; PharmaMar partly funded this project. Funding for open access charge: The CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI) |
| Databáze: | OpenAIRE |
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