View source for 7kfn


==Structure of Human Adenosine Deaminase Acting on dsRNA (ADAR2) bound to dsRNA containing a 2'-deoxy Benner's Base Z opposite the edited base==
<StructureSection load='7kfn' size='340' side='right'caption='[[7kfn]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7kfn]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KFN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KFN 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1W5:(1R)-1-(6-AMINO-2-HYDROXY-5-NITROPYRIDIN-3-YL)-1,4-ANHYDRO-2-DEOXY-5-O-PHOSPHONO-D-ERYTHRO-PENTITOL'>1W5</scene>, <scene name='pdbligand=8AZ:8-AZA-NEBULARINE-5-MONOPHOSPHATE'>8AZ</scene>, <scene name='pdbligand=IHP:INOSITOL+HEXAKISPHOSPHATE'>IHP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7kfn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kfn OCA], [https://pdbe.org/7kfn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kfn RCSB], [https://www.ebi.ac.uk/pdbsum/7kfn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kfn ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RED1_HUMAN RED1_HUMAN] Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing. This may affect gene expression and function in a number of ways that include mRNA translation by changing codons and hence the amino acid sequence of proteins; pre-mRNA splicing by altering splice site recognition sequences; RNA stability by changing sequences involved in nuclease recognition; genetic stability in the case of RNA virus genomes by changing sequences during viral RNA replication; and RNA structure-dependent activities such as microRNA production or targeting or protein-RNA interactions. Can edit both viral and cellular RNAs and can edit RNAs at multiple sites (hyper-editing) or at specific sites (site-specific editing). Its cellular RNA substrates include: bladder cancer-associated protein (BLCAP), neurotransmitter receptors for glutamate (GRIA2 and GRIK2) and serotonin (HTR2C), GABA receptor (GABRA3) and potassium voltage-gated channel (KCNA1). Site-specific RNA editing of transcripts encoding these proteins results in amino acid substitutions which consequently alter their functional activities. Edits GRIA2 at both the Q/R and R/G sites efficiently but converts the adenosine in hotspot1 much less efficiently. Can exert a proviral effect towards human immunodeficiency virus type 1 (HIV-1) and enhances its replication via both an editing-dependent and editing-independent mechanism. The former involves editing of adenosines in the 5'UTR while the latter occurs via suppression of EIF2AK2/PKR activation and function. Can inhibit cell proliferation and migration and can stimulate exocytosis.<ref>PMID:18178553</ref> <ref>PMID:19908260</ref> <ref>PMID:21289159</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Adenosine Deaminases Acting on RNA (ADARs) convert adenosine to inosine in double stranded RNA. Human ADARs can be directed to predetermined target sites in the transcriptome by complementary guide strands, allowing for the correction of disease-causing mutations at the RNA level. Here we use structural information available for ADAR2-RNA complexes to guide the design of nucleoside analogs for the position in the guide strand that contacts a conserved glutamic acid residue in ADARs (E488 in human ADAR2), which flips the adenosine into the ADAR active site for deamination. Mutating this residue to glutamine (E488Q) results in higher activity because of the hydrogen bond donating ability of Q488 to N3 of the orphan cytidine on the guide strand. We describe the evaluation of cytidine analogs for this position that stabilize an activated conformation of the enzyme-RNA complex and increase catalytic rate for deamination by the wild-type enzyme. A new crystal structure of ADAR2 bound to duplex RNA bearing a cytidine analog revealed a close contact between E488, stabilized by an additional hydrogen bond and altered charge distribution when compared to cytidine. In human cells and mouse primary liver fibroblasts, this single nucleotide modification increased directed editing yields when compared to an otherwise identical guide oligonucleotide. Our results show that modification of the guide RNA can mimic the effect of hyperactive mutants and advance the approach of recruiting endogenous ADARs for site-directed RNA editing.

Rational Design of RNA Editing Guide Strands: Cytidine Analogs at the Orphan Position.,Doherty EE, Wilcox XE, van Sint Fiet L, Kemmel C, Turunen JJ, Klein B, Tantillo DJ, Fisher AJ, Beal PA J Am Chem Soc. 2021 May 12;143(18):6865-6876. doi: 10.1021/jacs.0c13319. Epub , 2021 May 3. PMID:33939417<ref>PMID:33939417</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7kfn" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adenosine deaminase 3D structures|Adenosine deaminase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Beal PA]]
[[Category: Fisher AJ]]
[[Category: Wilcox XE]]