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==Structure of DDB1-CRBN-pomalidomide complex bound to IKZF1(ZF2)==
==Structure of DDB1-CRBN-pomalidomide complex bound to IKZF1(ZF2)==
<StructureSection load='6h0f' size='340' side='right' caption='[[6h0f]], [[Resolution|resolution]] 3.25&Aring;' scene=''>
<StructureSection load='6h0f' size='340' side='right'caption='[[6h0f]], [[Resolution|resolution]] 3.25&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6h0f]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H0F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H0F FirstGlance]. <br>
<table><tr><td colspan='2'>[[6h0f]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H0F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H0F FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Y70:S-POMALIDOMIDE'>Y70</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Y70:S-POMALIDOMIDE'>Y70</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDB1, XAP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CRBN, AD-006 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDB1, XAP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CRBN, AD-006 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), IKZF1, IK1, IKAROS, LYF1, ZNFN1A1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6h0f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h0f OCA], [http://pdbe.org/6h0f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6h0f RCSB], [http://www.ebi.ac.uk/pdbsum/6h0f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6h0f ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6h0f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h0f OCA], [http://pdbe.org/6h0f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6h0f RCSB], [http://www.ebi.ac.uk/pdbsum/6h0f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6h0f ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/CRBN_HUMAN CRBN_HUMAN]] Autosomal recessive nonsyndromic intellectual deficit;Distal monosomy 3p. The disease is caused by mutations affecting the gene represented in this entry.  
[[http://www.uniprot.org/uniprot/IKZF1_HUMAN IKZF1_HUMAN]] Precursor B-cell acute lymphoblastic leukemia;Stevens-Johnson syndrome;Pancytopenia due to IKZF1 mutations. Defects in IKZF1 are frequent occurrences (28.6%) in acute lymphoblasic leukemia (ALL). Such alterations or deletions lead to poor prognosis for ALL.  Chromosomal aberrations involving IKZF1 are a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;7)(q27;p12), with BCL6.  The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/CRBN_HUMAN CRBN_HUMAN]] Autosomal recessive nonsyndromic intellectual deficit;Distal monosomy 3p. The disease is caused by mutations affecting the gene represented in this entry.  
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/DDB1_HUMAN 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.<ref>PMID:12732143</ref> <ref>PMID:15448697</ref> <ref>PMID:14739464</ref> <ref>PMID:15882621</ref> <ref>PMID:16260596</ref> <ref>PMID:16482215</ref> <ref>PMID:17079684</ref> <ref>PMID:16407242</ref> <ref>PMID:16407252</ref> <ref>PMID:16678110</ref> <ref>PMID:16940174</ref> <ref>PMID:17041588</ref> <ref>PMID:16473935</ref> <ref>PMID:18593899</ref> <ref>PMID:18381890</ref> <ref>PMID:18332868</ref>  [[http://www.uniprot.org/uniprot/CRBN_HUMAN CRBN_HUMAN]] Component of some DCX (DDB1-CUL4-X-box) E3 protein ligase complex, a complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins and is required for limb outgrowth and expression of the fibroblast growth factor FGF8. In the complex, may act as a substrate receptor. Regulates the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1.<ref>PMID:18414909</ref> <ref>PMID:20223979</ref>   
[[http://www.uniprot.org/uniprot/IKZF1_HUMAN IKZF1_HUMAN]] Transcription regulator of hematopoietic cell differentiation (PubMed:17934067). Binds gamma-satellite DNA (PubMed:17135265, PubMed:19141594). Plays a role in the development of lymphocytes, B- and T-cells. Binds and activates the enhancer (delta-A element) of the CD3-delta gene. Repressor of the TDT (fikzfterminal deoxynucleotidyltransferase) gene during thymocyte differentiation. Regulates transcription through association with both HDAC-dependent and HDAC-independent complexes. Targets the 2 chromatin-remodeling complexes, NuRD and BAF (SWI/SNF), in a single complex (PYR complex), to the beta-globin locus in adult erythrocytes. Increases normal apoptosis in adult erythroid cells. Confers early temporal competence to retinal progenitor cells (RPCs) (By similarity). Function is isoform-specific and is modulated by dominant-negative inactive isoforms (PubMed:17135265, PubMed:17934067).[UniProtKB:Q03267]<ref>PMID:10204490</ref> <ref>PMID:17135265</ref> <ref>PMID:17934067</ref> <ref>PMID:19141594</ref>  [[http://www.uniprot.org/uniprot/CRBN_HUMAN CRBN_HUMAN]] Component of some DCX (DDB1-CUL4-X-box) E3 protein ligase complex, a complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins and is required for limb outgrowth and expression of the fibroblast growth factor FGF8. In the complex, may act as a substrate receptor. Regulates the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1.<ref>PMID:18414909</ref> <ref>PMID:20223979</ref>   
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Bunker, R D]]
[[Category: Bunker, R D]]
[[Category: Petzold, G]]
[[Category: Petzold, G]]

Latest revision as of 09:50, 17 April 2019

Structure of DDB1-CRBN-pomalidomide complex bound to IKZF1(ZF2)Structure of DDB1-CRBN-pomalidomide complex bound to IKZF1(ZF2)

Structural highlights

6h0f is a 12 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:DDB1, XAP1 (HUMAN), CRBN, AD-006 (HUMAN), IKZF1, IK1, IKAROS, LYF1, ZNFN1A1 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[IKZF1_HUMAN] Precursor B-cell acute lymphoblastic leukemia;Stevens-Johnson syndrome;Pancytopenia due to IKZF1 mutations. Defects in IKZF1 are frequent occurrences (28.6%) in acute lymphoblasic leukemia (ALL). Such alterations or deletions lead to poor prognosis for ALL. Chromosomal aberrations involving IKZF1 are a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;7)(q27;p12), with BCL6. The disease is caused by mutations affecting the gene represented in this entry. [CRBN_HUMAN] Autosomal recessive nonsyndromic intellectual deficit;Distal monosomy 3p. The disease is caused by mutations affecting the gene represented in this entry.

Function

[IKZF1_HUMAN] Transcription regulator of hematopoietic cell differentiation (PubMed:17934067). Binds gamma-satellite DNA (PubMed:17135265, PubMed:19141594). Plays a role in the development of lymphocytes, B- and T-cells. Binds and activates the enhancer (delta-A element) of the CD3-delta gene. Repressor of the TDT (fikzfterminal deoxynucleotidyltransferase) gene during thymocyte differentiation. Regulates transcription through association with both HDAC-dependent and HDAC-independent complexes. Targets the 2 chromatin-remodeling complexes, NuRD and BAF (SWI/SNF), in a single complex (PYR complex), to the beta-globin locus in adult erythrocytes. Increases normal apoptosis in adult erythroid cells. Confers early temporal competence to retinal progenitor cells (RPCs) (By similarity). Function is isoform-specific and is modulated by dominant-negative inactive isoforms (PubMed:17135265, PubMed:17934067).[UniProtKB:Q03267][1] [2] [3] [4] [CRBN_HUMAN] Component of some DCX (DDB1-CUL4-X-box) E3 protein ligase complex, a complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins and is required for limb outgrowth and expression of the fibroblast growth factor FGF8. In the complex, may act as a substrate receptor. Regulates the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1.[5] [6]

Publication Abstract from PubMed

The small molecules thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruiting a Cys2-His2 (C2H2) zinc finger domain to Cereblon (CRBN), the substrate receptor of the CRL4(CRBN) E3 ubiquitin ligase. We screened the human C2H2 zinc finger proteome for degradation in the presence of thalidomide analogs, identifying 11 zinc finger degrons. Structural and functional characterization of the C2H2 zinc finger degrons demonstrates how diverse zinc finger domains bind the permissive drug-CRBN interface. Computational zinc finger docking and biochemical analysis predict that more than 150 zinc fingers bind the drug-CRBN complex in vitro, and we show that selective zinc finger degradation can be achieved through compound modifications. Our results provide a rationale for therapeutically targeting transcription factors that were previously considered undruggable.

Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN.,Sievers QL, Petzold G, Bunker RD, Renneville A, Slabicki M, Liddicoat BJ, Abdulrahman W, Mikkelsen T, Ebert BL, Thoma NH Science. 2018 Nov 2;362(6414). pii: 362/6414/eaat0572. doi:, 10.1126/science.aat0572. PMID:30385546[7]

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

References

  1. ↑ Kim J, Sif S, Jones B, Jackson A, Koipally J, Heller E, Winandy S, Viel A, Sawyer A, Ikeda T, Kingston R, Georgopoulos K. Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity. 1999 Mar;10(3):345-55. PMID:10204490
  2. ↑ Ronni T, Payne KJ, Ho S, Bradley MN, Dorsam G, Dovat S. Human Ikaros function in activated T cells is regulated by coordinated expression of its largest isoforms. J Biol Chem. 2007 Jan 26;282(4):2538-47. doi: 10.1074/jbc.M605627200. Epub 2006, Nov 29. PMID:17135265 doi:http://dx.doi.org/10.1074/jbc.M605627200
  3. ↑ Dijon M, Bardin F, Murati A, Batoz M, Chabannon C, Tonnelle C. The role of Ikaros in human erythroid differentiation. Blood. 2008 Feb 1;111(3):1138-46. doi: 10.1182/blood-2007-07-098202. Epub 2007, Oct 12. PMID:17934067 doi:http://dx.doi.org/10.1182/blood-2007-07-098202
  4. ↑ Kim JH, Ebersole T, Kouprina N, Noskov VN, Ohzeki J, Masumoto H, Mravinac B, Sullivan BA, Pavlicek A, Dovat S, Pack SD, Kwon YW, Flanagan PT, Loukinov D, Lobanenkov V, Larionov V. Human gamma-satellite DNA maintains open chromatin structure and protects a transgene from epigenetic silencing. Genome Res. 2009 Apr;19(4):533-44. Epub 2009 Jan 13. PMID:19141594 doi:http://dx.doi.org/gr.086496.108
  5. ↑ Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM. Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation. Neurogenetics. 2008 Jul;9(3):219-23. doi: 10.1007/s10048-008-0128-2. Epub 2008, Apr 15. PMID:18414909 doi:http://dx.doi.org/10.1007/s10048-008-0128-2
  6. ↑ Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H. Identification of a primary target of thalidomide teratogenicity. Science. 2010 Mar 12;327(5971):1345-50. doi: 10.1126/science.1177319. PMID:20223979 doi:http://dx.doi.org/10.1126/science.1177319
  7. ↑ Sievers QL, Petzold G, Bunker RD, Renneville A, Slabicki M, Liddicoat BJ, Abdulrahman W, Mikkelsen T, Ebert BL, Thoma NH. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science. 2018 Nov 2;362(6414). pii: 362/6414/eaat0572. doi:, 10.1126/science.aat0572. PMID:30385546 doi:http://dx.doi.org/10.1126/science.aat0572

6h0f, resolution 3.25Å

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