6d06

From Proteopedia

(Difference between revisions)

Revision as of 08:19, 6 March 2019

Human ADAR2d E488Y mutant complexed with dsRNA containing an abasic site opposite the edited base

Structural highlights

6d06 is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:	,
Gene:	ADARB1, ADAR2, DRADA2, RED1 (HUMAN)
Activity:	Double-stranded RNA adenine deaminase, with EC number 3.5.4.37
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

Molecules capable of directing changes to nucleic acid sequences are powerful tools for molecular biology and promising candidates for the therapeutic correction of disease-causing mutations. However, unwanted reactions at off-target sites complicate their use. Here we report selective combinations of mutant editing enzyme and directing oligonucleotide. Mutations in human ADAR2 (adenosine deaminase acting on RNA 2) that introduce aromatic amino acids at position 488 reduce background RNA editing. This residue is juxtaposed to the nucleobase that pairs with the editing site adenine, suggesting a steric clash for the bulky mutants. Replacing this nucleobase with a hydrogen atom removes the clash and restores editing activity. A crystal structure of the E488Y mutant bound to abasic site-containing RNA shows the accommodation of the tyrosine side chain. Finally, we demonstrate directed RNA editing in vitro and in human cells using mutant ADAR2 proteins and modified guide RNAs with reduced off-target activity.

A Bump-Hole Approach for Directed RNA Editing.,Monteleone LR, Matthews MM, Palumbo CM, Thomas JM, Zheng Y, Chiang Y, Fisher AJ, Beal PA Cell Chem Biol. 2018 Nov 23. pii: S2451-9456(18)30385-4. doi:, 10.1016/j.chembiol.2018.10.025. PMID:30581135^[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
↑ Monteleone LR, Matthews MM, Palumbo CM, Thomas JM, Zheng Y, Chiang Y, Fisher AJ, Beal PA. A Bump-Hole Approach for Directed RNA Editing. Cell Chem Biol. 2018 Nov 23. pii: S2451-9456(18)30385-4. doi:, 10.1016/j.chembiol.2018.10.025. PMID:30581135 doi:http://dx.doi.org/10.1016/j.chembiol.2018.10.025

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6d06"

@@ Line 1: / Line 1: @@
 ==Human ADAR2d E488Y mutant complexed with dsRNA containing an abasic site opposite the edited base==
-<StructureSection load='6d06' size='340' side='right' caption='[[6d06]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
+<StructureSection load='6d06' size='340' side='right'  caption='[[6d06]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6d06]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D06 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D06 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6d06]] 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=6D06 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D06 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IHP:INOSITOL+HEXAKISPHOSPHATE'>IHP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=8AZ:8-AZA-NEBULARINE-5-MONOPHOSPHATE'>8AZ</scene>, <scene name='pdbligand=N:ANY+5-MONOPHOSPHATE+NUCLEOTIDE'>N</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADARB1, ADAR2, DRADA2, RED1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Double-stranded_RNA_adenine_deaminase Double-stranded RNA adenine deaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.4.37 3.5.4.37] </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=6d06 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d06 OCA], [http://pdbe.org/6d06 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d06 RCSB], [http://www.ebi.ac.uk/pdbsum/6d06 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d06 ProSAT]</span></td></tr>
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 6d06" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Adenosine deaminase 3D structures|Adenosine deaminase 3D structures]]
 == References ==
 <references/>
@@ Line 25: / Line 29: @@
 </StructureSection>
 [[Category: Double-stranded RNA adenine deaminase]]
+[[Category: Human]]
 [[Category: Beal, P A]]
 [[Category: Fisher, A J]]

6d06

From Proteopedia

Revision as of 08:19, 6 March 2019

Human ADAR2d E488Y mutant complexed with dsRNA containing an abasic site opposite the edited base

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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