6q0w

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Structure of DDB1-DDA1-DCAF15 complex bound to Indisulam and RBM39

Structural highlights

6q0w is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.9Å
Ligands:EF6, ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DDB1_HUMAN Required for DNA repair. Binds to DDB2 to form the UV-damaged DNA-binding protein complex (the UV-DDB complex). The UV-DDB complex may recognize UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair. The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches. Also appears to function as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the DCX E3 ubiquitin-protein ligase complex is determined by the variable substrate recognition component recruited by DDB1. DCX(DDB2) (also known as DDB1-CUL4-ROC1, CUL4-DDB-ROC1 and CUL4-DDB-RBX1) may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage. The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair. DCX(DDB2) also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(ERCC8) (the CSA complex) plays a role in transcription-coupled repair (TCR). May also play a role in ubiquitination of CDKN1B/p27kip when associated with CUL4 and SKP2.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]

Publication Abstract from PubMed

The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at a resolution of 4.4 A, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.

Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15.,Faust TB, Yoon H, Nowak RP, Donovan KA, Li Z, Cai Q, Eleuteri NA, Zhang T, Gray NS, Fischer ES Nat Chem Biol. 2019 Nov 4. pii: 10.1038/s41589-019-0378-3. doi:, 10.1038/s41589-019-0378-3. PMID:31686031[17]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
28 reviews cite this structure
PROTAC targeted protein degraders: the past is prologue.
Békés et al. (2022)
27 more
23 other articles
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See Also

References

  1. ↑ Groisman R, Polanowska J, Kuraoka I, Sawada J, Saijo M, Drapkin R, Kisselev AF, Tanaka K, Nakatani Y. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell. 2003 May 2;113(3):357-67. PMID:12732143
  2. ↑ Hu J, McCall CM, Ohta T, Xiong Y. Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nat Cell Biol. 2004 Oct;6(10):1003-9. Epub 2004 Sep 26. PMID:15448697 doi:10.1038/ncb1172
  3. ↑ Wertz IE, O'Rourke KM, Zhang Z, Dornan D, Arnott D, Deshaies RJ, Dixit VM. Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. Science. 2004 Feb 27;303(5662):1371-4. Epub 2004 Jan 22. PMID:14739464 doi:10.1126/science.1093549
  4. ↑ Sugasawa K, Okuda Y, Saijo M, Nishi R, Matsuda N, Chu G, Mori T, Iwai S, Tanaka K, Tanaka K, Hanaoka F. UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex. Cell. 2005 May 6;121(3):387-400. PMID:15882621 doi:10.1016/j.cell.2005.02.035
  5. ↑ Kulaksiz G, Reardon JT, Sancar A. Xeroderma pigmentosum complementation group E protein (XPE/DDB2): purification of various complexes of XPE and analyses of their damaged DNA binding and putative DNA repair properties. Mol Cell Biol. 2005 Nov;25(22):9784-92. PMID:16260596 doi:10.1128/MCB.25.22.9784-9792.2005
  6. ↑ Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C, Tsurimoto T, Nakayama KI, Nakayama K, Fujita M, Lygerou Z, Nishimoto T. Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. EMBO J. 2006 Mar 8;25(5):1126-36. Epub 2006 Feb 16. PMID:16482215 doi:7601002
  7. ↑ He YJ, McCall CM, Hu J, Zeng Y, Xiong Y. DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-ROC1 ubiquitin ligases. Genes Dev. 2006 Nov 1;20(21):2949-54. PMID:17079684 doi:20/21/2949
  8. ↑ Hu J, Xiong Y. An evolutionarily conserved function of proliferating cell nuclear antigen for Cdt1 degradation by the Cul4-Ddb1 ubiquitin ligase in response to DNA damage. J Biol Chem. 2006 Feb 17;281(7):3753-6. Epub 2006 Jan 3. PMID:16407242 doi:10.1074/jbc.C500464200
  9. ↑ Senga T, Sivaprasad U, Zhu W, Park JH, Arias EE, Walter JC, Dutta A. PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination. J Biol Chem. 2006 Mar 10;281(10):6246-52. Epub 2006 Jan 9. PMID:16407252 doi:M512705200
  10. ↑ Wang H, Zhai L, Xu J, Joo HY, Jackson S, Erdjument-Bromage H, Tempst P, Xiong Y, Zhang Y. Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol Cell. 2006 May 5;22(3):383-94. PMID:16678110 doi:S1097-2765(06)00230-9
  11. ↑ Lovejoy CA, Lock K, Yenamandra A, Cortez D. DDB1 maintains genome integrity through regulation of Cdt1. Mol Cell Biol. 2006 Nov;26(21):7977-90. Epub 2006 Aug 28. PMID:16940174 doi:MCB.00819-06
  12. ↑ Higa LA, Wu M, Ye T, Kobayashi R, Sun H, Zhang H. CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nat Cell Biol. 2006 Nov;8(11):1277-83. Epub 2006 Oct 15. PMID:17041588 doi:10.1038/ncb1490
  13. ↑ Kapetanaki MG, Guerrero-Santoro J, Bisi DC, Hsieh CL, Rapic-Otrin V, Levine AS. The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderma pigmentosum group E and targets histone H2A at UV-damaged DNA sites. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2588-93. Epub 2006 Feb 10. PMID:16473935 doi:10.1073/pnas.0511160103
  14. ↑ Guerrero-Santoro J, Kapetanaki MG, Hsieh CL, Gorbachinsky I, Levine AS, Rapic-Otrin V. The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A. Cancer Res. 2008 Jul 1;68(13):5014-22. PMID:18593899 doi:68/13/5014
  15. ↑ Hu J, Zacharek S, He YJ, Lee H, Shumway S, Duronio RJ, Xiong Y. WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase. Genes Dev. 2008 Apr 1;22(7):866-71. doi: 10.1101/gad.1624008. PMID:18381890 doi:10.1101/gad.1624008
  16. ↑ Huang J, Chen J. VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. Oncogene. 2008 Jul 3;27(29):4056-64. Epub 2008 Mar 10. PMID:18332868 doi:onc200844
  17. ↑ Faust TB, Yoon H, Nowak RP, Donovan KA, Li Z, Cai Q, Eleuteri NA, Zhang T, Gray NS, Fischer ES. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat Chem Biol. 2019 Nov 4. pii: 10.1038/s41589-019-0378-3. doi:, 10.1038/s41589-019-0378-3. PMID:31686031 doi:http://dx.doi.org/10.1038/s41589-019-0378-3

Contents


PDB ID 6q0w

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