View source for 4tu7


==Structure of U2AF65 D231V variant with BrU5 DNA==
<StructureSection load='4tu7' size='340' side='right'caption='[[4tu7]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4tu7]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TU7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TU7 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.087&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BRU:5-BROMO-2-DEOXYURIDINE-5-MONOPHOSPHATE'>BRU</scene>, <scene name='pdbligand=CPQ:N,N-BIS(3-D-GLUCONAMIDOPROPYL)DEOXYCHOLAMIDE'>CPQ</scene>, <scene name='pdbligand=DIO:1,4-DIETHYLENE+DIOXIDE'>DIO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=4tu7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tu7 OCA], [https://pdbe.org/4tu7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tu7 RCSB], [https://www.ebi.ac.uk/pdbsum/4tu7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tu7 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/U2AF2_HUMAN U2AF2_HUMAN] Necessary for the splicing of pre-mRNA. Induces cardiac troponin-T (TNNT2) pre-mRNA exon inclusion in muscle. Regulates the TNNT2 exon 5 inclusion through competition with MBNL1. Binds preferentially to a single-stranded structure within the polypyrimidine tract of TNNT2 intron 4 during spliceosome assembly. Required for the export of mRNA out of the nucleus, even if the mRNA is encoded by an intron-less gene. Represses the splicing of MAPT/Tau exon 10.<ref>PMID:15009664</ref> <ref>PMID:19470458</ref> <ref>PMID:19574390</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Purine interruptions of polypyrimidine (Py) tract splice site signals contribute to human genetic diseases. The essential splicing factor U2AF65 normally recognizes a Py tract consensus sequence preceding the major class of 3' splice sites. We found that neurofibromatosis- or retinitis pigmentosa-causing mutations in the 5' regions of Py tracts severely reduce U2AF65 affinity. Conversely, we identified a preferred binding site of U2AF65 for purine substitutions in the 3' regions of Py tracts. Based on a comparison of new U2AF65 structures bound to either A- or G-containing Py tracts with previously identified pyrimidine-containing structures, we expected to find that a D231V amino acid change in U2AF65 would specify U over other nucleotides. We found that the crystal structure of the U2AF65-D231V variant confirms favorable packing between the engineered valine and a target uracil base. The D231V amino acid change restores U2AF65 affinity for two mutated splice sites that cause human genetic diseases and successfully promotes splicing of a defective retinitis pigmentosa-causing transcript. We conclude that reduced U2AF65 binding is a molecular consequence of disease-relevant mutations, and that a structure-guided U2AF65 variant is capable of manipulating gene expression in eukaryotic cells.

Structure-guided U2AF65 variant improves recognition and splicing of a defective pre-mRNA.,Agrawal AA, McLaughlin KJ, Jenkins JL, Kielkopf CL Proc Natl Acad Sci U S A. 2014 Nov 24. pii: 201412743. PMID:25422459<ref>PMID:25422459</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4tu7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Agrawal AA]]
[[Category: Jenkins JL]]
[[Category: Kielkopf CL]]