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8e4x

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Human Adenosine Deaminase Acting on dsRNA (ADAR2-R2D) bound to dsRNA containing a G:3-deaza dA pair adjacent to the target site

Structural highlights

8e4x is a 4 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 2.8Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3]

Publication Abstract from PubMed

ADARs (adenosine deaminases acting on RNA) can be directed to sites in the transcriptome by complementary guide strands allowing for the correction of disease-causing mutations at the RNA level. However, ADARs show bias against editing adenosines with a guanosine 5' nearest neighbor (5'-GA sites), limiting the scope of this approach. Earlier studies suggested this effect arises from a clash in the RNA minor groove involving the 2-amino group of the guanosine adjacent to an editing site. Here we show that nucleosides capable of pairing with guanosine in a syn conformation enhance editing for 5'-GA sites. We describe the crystal structure of a fragment of human ADAR2 bound to RNA bearing a G:G pair adjacent to an editing site. The two guanosines form a Gsyn:Ganti pair solving the steric problem by flipping the 2-amino group of the guanosine adjacent to the editing site into the major groove. Also, duplexes with 2'-deoxyadenosine and 3-deaza-2'-deoxyadenosine displayed increased editing efficiency, suggesting the formation of a Gsyn:AH+anti pair. This was supported by X-ray crystallography of an ADAR complex with RNA bearing a G:3-deaza dA pair. This study shows how non-Watson-Crick pairing in duplex RNA can facilitate ADAR editing enabling the design of next generation guide strands for therapeutic RNA editing.

ADAR activation by inducing a syn conformation at guanosine adjacent to an editing site.,Doherty EE, Karki A, Wilcox XE, Mendoza HG, Manjunath A, Matos VJ, Fisher AJ, Beal PA Nucleic Acids Res. 2022 Oct 16. pii: 6761749. doi: 10.1093/nar/gkac897. PMID:36243986^[4]

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

References

↑ Cenci C, Barzotti R, Galeano F, Corbelli S, Rota R, Massimi L, Di Rocco C, O'Connell MA, Gallo A. Down-regulation of RNA editing in pediatric astrocytomas: ADAR2 editing activity inhibits cell migration and proliferation. J Biol Chem. 2008 Mar 14;283(11):7251-60. doi: 10.1074/jbc.M708316200. Epub 2008 , Jan 4. PMID:18178553 doi:http://dx.doi.org/10.1074/jbc.M708316200
↑ Galeano F, Leroy A, Rossetti C, Gromova I, Gautier P, Keegan LP, Massimi L, Di Rocco C, O'Connell MA, Gallo A. Human BLCAP transcript: new editing events in normal and cancerous tissues. Int J Cancer. 2010 Jul 1;127(1):127-37. doi: 10.1002/ijc.25022. PMID:19908260 doi:10.1002/ijc.25022
↑ Doria M, Tomaselli S, Neri F, Ciafre SA, Farace MG, Michienzi A, Gallo A. ADAR2 editing enzyme is a novel human immunodeficiency virus-1 proviral factor. J Gen Virol. 2011 May;92(Pt 5):1228-32. doi: 10.1099/vir.0.028043-0. Epub 2011, Feb 2. PMID:21289159 doi:10.1099/vir.0.028043-0
↑ Doherty EE, Karki A, Wilcox XE, Mendoza HG, Manjunath A, Matos VJ, Fisher AJ, Beal PA. ADAR activation by inducing a syn conformation at guanosine adjacent to an editing site. Nucleic Acids Res. 2022 Oct 16. pii: 6761749. doi: 10.1093/nar/gkac897. PMID:36243986 doi:http://dx.doi.org/10.1093/nar/gkac897

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/8e4x"

Categories: Homo sapiens | Large Structures | Fisher AJ | Mendoza HG

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[8e4x]] 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=8E4X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E4X FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4DU:1-(2-DEOXY-5-O-PHOSPHONO-BETA-D-ERYTHRO-PENTOFURANOSYL)-1H-IMIDAZO[4,5-C]PYRIDIN-4-AMINE'>4DU</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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4DU:1-(2-DEOXY-5-O-PHOSPHONO-BETA-D-ERYTHRO-PENTOFURANOSYL)-1H-IMIDAZO[4,5-C]PYRIDIN-4-AMINE'>4DU</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=8e4x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e4x OCA], [https://pdbe.org/8e4x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e4x RCSB], [https://www.ebi.ac.uk/pdbsum/8e4x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e4x ProSAT]</span></td></tr>
 </table>

8e4x

From Proteopedia

Current revision

Human Adenosine Deaminase Acting on dsRNA (ADAR2-R2D) bound to dsRNA containing a G:3-deaza dA pair adjacent to the target site

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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