6slo

From Proteopedia

(Difference between revisions)

Revision as of 12:43, 24 January 2024

Crystal structure of PUF60 UHM domain in complex with 7,8 dimethoxyperphenazine

Structural highlights

6slo is a 4 chain structure with sequence from Citrobacter freundii MGH 56 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.94Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PUF60_HUMAN DNA- and RNA-binding protein, involved in several nuclear processes such as pre-mRNA splicing, apoptosis and transcription regulation. In association with FUBP1 regulates MYC transcription at the P2 promoter through the core-TFIIH basal transcription factor. Acts as a transcriptional repressor through the core-TFIIH basal transcription factor. Represses FUBP1-induced transcriptional activation but not basal transcription. Decreases ERCC3 helicase activity. Does not repress TFIIH-mediated transcription in xeroderma pigmentosum complementation group B (XPB) cells. Is also involved in pre-mRNA splicing. Promotes splicing of an intron with weak 3'-splice site and pyrimidine tract in a cooperative manner with U2AF2. Involved in apoptosis induction when overexpressed in HeLa cells. Isoform 6 failed to repress MYC transcription and inhibited FIR-induced apoptosis in colorectal cancer. Isoform 6 may contribute to tumor progression by enabling increased MYC expression and greater resistance to apoptosis in tumors than in normal cells. Modulates alternative splicing of several mRNAs. Binds to relaxed DNA of active promoter regions. Binds to the pyrimidine tract and 3'-splice site regions of pre-mRNA; binding is enhanced in presence of U2AF2. Binds to Y5 RNA in association with TROVE2. Binds to poly(U) RNA.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] A0A064CXU8_CITFR

Publication Abstract from PubMed

Interactions between U2AF homology motifs (UHMs) and U2AF ligand motifs (ULMs) play a crucial role in early spliceosome assembly in eukaryotic gene regulation. UHM-ULM interactions mediate heterodimerization of the constitutive splicing factors U2AF65 and U2AF35 and between other splicing factors that regulate spliceosome assembly at the 3' splice site, where UHM domains of alternative splicing factors, such as SPF45 and PUF60, contribute to alternative splicing regulation. Here, we performed high-throughput screening using fluorescence polarization assays with hit validation by NMR and identified phenothiazines as general inhibitors of UHM-ULM interactions. NMR studies show that these compounds occupy the tryptophan binding pocket of UHM domains. Co-crystal structures of the inhibitors with the PUF60 UHM domain and medicinal chemistry provide structure-activity-relationships and reveal functional groups important for binding. These inhibitors inhibit early spliceosome assembly on pre-mRNA substrates in vitro. Our data show that spliceosome assembly can be inhibited by targeting UHM-ULM interactions by small molecules, thus extending the toolkit of splicing modulators for structural and biochemical studies of the spliceosome and splicing regulation.

Identification of phenothiazine derivatives as UHM-binding inhibitors of early spliceosome assembly.,Jagtap PKA, Kubelka T, Soni K, Will CL, Garg D, Sippel C, Kapp TG, Potukuchi HK, Schorpp K, Hadian K, Kessler H, Luhrmann R, Hausch F, Bach T, Sattler M Nat Commun. 2020 Nov 6;11(1):5621. doi: 10.1038/s41467-020-19514-1. PMID:33159082^[7]

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

References

↑ Liu J, He L, Collins I, Ge H, Libutti D, Li J, Egly JM, Levens D. The FBP interacting repressor targets TFIIH to inhibit activated transcription. Mol Cell. 2000 Feb;5(2):331-41. PMID:10882074
↑ Page-McCaw PS, Amonlirdviman K, Sharp PA. PUF60: a novel U2AF65-related splicing activity. RNA. 1999 Dec;5(12):1548-60. PMID:10606266
↑ Liu J, Akoulitchev S, Weber A, Ge H, Chuikov S, Libutti D, Wang XW, Conaway JW, Harris CC, Conaway RC, Reinberg D, Levens D. Defective interplay of activators and repressors with TFIH in xeroderma pigmentosum. Cell. 2001 Feb 9;104(3):353-63. PMID:11239393
↑ Matsushita K, Tomonaga T, Shimada H, Shioya A, Higashi M, Matsubara H, Harigaya K, Nomura F, Libutti D, Levens D, Ochiai T. An essential role of alternative splicing of c-myc suppressor FUSE-binding protein-interacting repressor in carcinogenesis. Cancer Res. 2006 Feb 1;66(3):1409-17. PMID:16452196 doi:http://dx.doi.org/10.1158/0008-5472.CAN-04-4459
↑ Liu J, Kouzine F, Nie Z, Chung HJ, Elisha-Feil Z, Weber A, Zhao K, Levens D. The FUSE/FBP/FIR/TFIIH system is a molecular machine programming a pulse of c-myc expression. EMBO J. 2006 May 17;25(10):2119-30. Epub 2006 Apr 20. PMID:16628215 doi:http://dx.doi.org/7601101
↑ Hastings ML, Allemand E, Duelli DM, Myers MP, Krainer AR. Control of pre-mRNA splicing by the general splicing factors PUF60 and U2AF65. PLoS One. 2007 Jun 20;2(6):e538. PMID:17579712 doi:http://dx.doi.org/10.1371/journal.pone.0000538
↑ Jagtap PKA, Kubelka T, Soni K, Will CL, Garg D, Sippel C, Kapp TG, Potukuchi HK, Schorpp K, Hadian K, Kessler H, Luhrmann R, Hausch F, Bach T, Sattler M. Identification of phenothiazine derivatives as UHM-binding inhibitors of early spliceosome assembly. Nat Commun. 2020 Nov 6;11(1):5621. doi: 10.1038/s41467-020-19514-1. PMID:33159082 doi:http://dx.doi.org/10.1038/s41467-020-19514-1

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6slo"

@@ Line 3: / Line 3: @@
 <StructureSection load='6slo' size='340' side='right'caption='[[6slo]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6slo]] is a 4 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=6SLO OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6SLO FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6slo]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Citrobacter_freundii_MGH_56 Citrobacter freundii MGH 56] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SLO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SLO FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LJT:2-[4-[3-(8-chloranyl-2,3-dimethoxy-phenothiazin-10-yl)propyl]piperazin-1-yl]ethanol'>LJT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.94&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PUF60, FIR, ROBPI, SIAHBP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LJT:2-[4-[3-(8-chloranyl-2,3-dimethoxy-phenothiazin-10-yl)propyl]piperazin-1-yl]ethanol'>LJT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6slo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6slo OCA], [http://pdbe.org/6slo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6slo RCSB], [http://www.ebi.ac.uk/pdbsum/6slo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6slo ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6slo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6slo OCA], [https://pdbe.org/6slo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6slo RCSB], [https://www.ebi.ac.uk/pdbsum/6slo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6slo ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/PUF60_HUMAN PUF60_HUMAN] DNA- and RNA-binding protein, involved in several nuclear processes such as pre-mRNA splicing, apoptosis and transcription regulation. In association with FUBP1 regulates MYC transcription at the P2 promoter through the core-TFIIH basal transcription factor. Acts as a transcriptional repressor through the core-TFIIH basal transcription factor. Represses FUBP1-induced transcriptional activation but not basal transcription. Decreases ERCC3 helicase activity. Does not repress TFIIH-mediated transcription in xeroderma pigmentosum complementation group B (XPB) cells. Is also involved in pre-mRNA splicing. Promotes splicing of an intron with weak 3'-splice site and pyrimidine tract in a cooperative manner with U2AF2. Involved in apoptosis induction when overexpressed in HeLa cells. Isoform 6 failed to repress MYC transcription and inhibited FIR-induced apoptosis in colorectal cancer. Isoform 6 may contribute to tumor progression by enabling increased MYC expression and greater resistance to apoptosis in tumors than in normal cells. Modulates alternative splicing of several mRNAs. Binds to relaxed DNA of active promoter regions. Binds to the pyrimidine tract and 3'-splice site regions of pre-mRNA; binding is enhanced in presence of U2AF2. Binds to Y5 RNA in association with TROVE2. Binds to poly(U) RNA.<ref>PMID:10882074</ref> <ref>PMID:10606266</ref> <ref>PMID:11239393</ref> <ref>PMID:16452196</ref> <ref>PMID:16628215</ref> <ref>PMID:17579712</ref> [https://www.uniprot.org/uniprot/A0A064CXU8_CITFR A0A064CXU8_CITFR]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Citrobacter freundii MGH 56]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Bach, T]]
+[[Category: Bach T]]
-[[Category: Jagtap, P K.A]]
+[[Category: Jagtap PKA]]
-[[Category: Kubelka, T]]
+[[Category: Kubelka T]]
-[[Category: Sattler, M]]
+[[Category: Sattler M]]
-[[Category: Splicing]]
-[[Category: Splicing inhibitor]]
-[[Category: Uhm domain]]

6slo

From Proteopedia

Revision as of 12:43, 24 January 2024

Crystal structure of PUF60 UHM domain in complex with 7,8 dimethoxyperphenazine

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox