6RRC
Crystal structure of the N-terminal region of human cohesin subunit STAG1 in complex with RAD21 peptide
Summary for 6RRC
| Entry DOI | 10.2210/pdb6rrc/pdb |
| Descriptor | Cohesin subunit SA-1, Double-strand-break repair protein rad21 homolog, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | cohesin, sa-1, chromosome segregation, gene regulation |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 85442.00 |
| Authors | Newman, J.A.,Katis, V.L.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.,Bountra, C.,Gileadi, O. (deposition date: 2019-05-17, release date: 2019-06-19, Last modification date: 2024-01-24) |
| Primary citation | van der Lelij, P.,Newman, J.A.,Lieb, S.,Jude, J.,Katis, V.,Hoffmann, T.,Hinterndorfer, M.,Bader, G.,Kraut, N.,Pearson, M.A.,Peters, J.M.,Zuber, J.,Gileadi, O.,Petronczki, M. STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers. Life Sci Alliance, 3:-, 2020 Cited by PubMed Abstract: The cohesin subunit has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed a synthetic lethal interaction between and its paralog To systematically probe genetic vulnerabilities in the absence of STAG2, we have performed genome-wide CRISPR screens in isogenic cell lines and identified STAG1 as the most prominent and selective dependency of STAG2-deficient cells. Using an inducible degron system, we show that chemical genetic degradation of STAG1 protein results in the loss of sister chromatid cohesion and rapid cell death in STAG2-deficient cells, while sparing -wild-type cells. Biochemical assays and X-ray crystallography identify STAG1 regions that interact with the RAD21 subunit of the cohesin complex. STAG1 mutations that abrogate this interaction selectively compromise the viability of -deficient cells. Our work highlights the degradation of STAG1 and inhibition of its interaction with RAD21 as promising therapeutic strategies. These findings lay the groundwork for the development of STAG1-directed small molecules to exploit synthetic lethality in -mutated tumors. PubMed: 32467316DOI: 10.26508/lsa.202000725 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.37 Å) |
Structure validation
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