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-Structure paper
タイトル | Cryo-EM Structure of Nucleotide-Bound Tel1 Unravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations. |
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ジャーナル・号・ページ | Structure, Vol. 28, Issue 1, Page 96-104.e3, Year 2020 |
掲載日 | 2020年1月7日 |
著者 | Luke A Yates / Rhys M Williams / Sarem Hailemariam / Rafael Ayala / Peter Burgers / Xiaodong Zhang / |
PubMed 要旨 | Yeast Tel1 and its highly conserved human ortholog ataxia-telangiectasia mutated (ATM) are large protein kinases central to the maintenance of genome integrity. Mutations in ATM are found in ataxia- ...Yeast Tel1 and its highly conserved human ortholog ataxia-telangiectasia mutated (ATM) are large protein kinases central to the maintenance of genome integrity. Mutations in ATM are found in ataxia-telangiectasia (A-T) patients and ATM is one of the most frequently mutated genes in many cancers. Using cryoelectron microscopy, we present the structure of Tel1 in a nucleotide-bound state. Our structure reveals molecular details of key residues surrounding the nucleotide binding site and provides a structural and molecular basis for its intrinsically low basal activity. We show that the catalytic residues are in a productive conformation for catalysis, but the phosphatidylinositol 3-kinase-related kinase (PIKK) regulatory domain insert restricts peptide substrate access and the N-lobe is in an open conformation, thus explaining the requirement for Tel1 activation. Structural comparisons with other PIKKs suggest a conserved and common allosteric activation mechanism. Our work also provides a structural rationale for many mutations found in A-T and cancer. |
リンク | Structure / PubMed:31740029 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 4.0 Å |
構造データ | EMDB-10120, PDB-6s8f: |
化合物 | ChemComp-ANP: ChemComp-MG: |
由来 |
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キーワード | HYDROLASE / Kinase / DNA Damage Response / CryoEM / Phosphatidylinositol-3-kinase-like kinase |