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4nj4

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Revision as of 08:30, 11 January 2023

Crystal Structure of Human ALKBH5

Structural highlights

4nj4 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ALKB5_HUMAN Dioxygenase that demethylates RNA by oxidative demethylation: specifically demethylates N(6)-methyladenosine (m(6)A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Requires molecular oxygen, alpha-ketoglutarate and iron. Demethylation of m(6)A mRNA affects mRNA processing and export and is required for spermatogenesis.^[1] ^[2]

Publication Abstract from PubMed

ALKBH5 is a 2-oxoglutarate (2OG) and ferrous iron-dependent nucleic acid oxygenase (NAOX) that catalyzes the demethylation of N(6)-methyladenine in RNA. ALKBH5 is upregulated under hypoxia and plays a role in spermatogenesis. We describe a crystal structure of human ALKBH5 (residues 66-292) to 2.0 A resolution. ALKBH566-292 has a double-stranded beta-helix core fold as observed in other 2OG and iron-dependent oxygenase family members. The active site metal is octahedrally coordinated by an HXD...H motif (comprising residues His204, Asp206 and His266) and three water molecules. ALKBH5 shares a nucleotide recognition lid and conserved active site residues with other NAOXs. A large loop (betaIV-V) in ALKBH5 occupies a similar region as the L1 loop of the fat mass and obesity-associated protein that is proposed to confer single-stranded RNA selectivity. Unexpectedly, a small molecule inhibitor, IOX3, was observed covalently attached to the side chain of Cys200 located outside of the active site. Modelling substrate into the active site based on other NAOX-nucleic acid complexes reveals conserved residues important for recognition and demethylation mechanisms. The structural insights will aid in the development of inhibitors selective for NAOXs, for use as functional probes and for therapeutic benefit.

Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation.,Aik W, Scotti JS, Choi H, Gong L, Demetriades M, Schofield CJ, McDonough MA Nucleic Acids Res. 2014 Apr 1;42(7):4741-54. doi: 10.1093/nar/gku085. Epub 2014, Jan 30. PMID:24489119^[3]

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

References

↑ Thalhammer A, Bencokova Z, Poole R, Loenarz C, Adam J, O'Flaherty L, Schodel J, Mole D, Giaslakiotis K, Schofield CJ, Hammond EM, Ratcliffe PJ, Pollard PJ. Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1alpha (HIF-1alpha). PLoS One. 2011 Jan 14;6(1):e16210. doi: 10.1371/journal.pone.0016210. PMID:21264265 doi:http://dx.doi.org/10.1371/journal.pone.0016210
↑ Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vagbo CB, Shi Y, Wang WL, Song SH, Lu Z, Bosmans RP, Dai Q, Hao YJ, Yang X, Zhao WM, Tong WM, Wang XJ, Bogdan F, Furu K, Fu Y, Jia G, Zhao X, Liu J, Krokan HE, Klungland A, Yang YG, He C. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013 Jan 10;49(1):18-29. doi: 10.1016/j.molcel.2012.10.015. Epub 2012, Nov 21. PMID:23177736 doi:http://dx.doi.org/10.1016/j.molcel.2012.10.015
↑ Aik W, Scotti JS, Choi H, Gong L, Demetriades M, Schofield CJ, McDonough MA. Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation. Nucleic Acids Res. 2014 Apr 1;42(7):4741-54. doi: 10.1093/nar/gku085. Epub 2014, Jan 30. PMID:24489119 doi:http://dx.doi.org/10.1093/nar/gku085

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/4nj4"

Categories: Homo sapiens | Large Structures | Aik WS | McDonough MA | Schofield CJ

@@ Line 1: / Line 1: @@
 ==Crystal Structure of Human ALKBH5==
-<StructureSection load='4nj4' size='340' side='right' caption='[[4nj4]], [[Resolution|resolution]] 2.02&Aring;' scene=''>
+<StructureSection load='4nj4' size='340' side='right'caption='[[4nj4]], [[Resolution|resolution]] 2.02&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4nj4]] is a 2 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=4NJ4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NJ4 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4nj4]] is a 2 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=4NJ4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NJ4 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=UN9:N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)CARBONYL]GLYCINE'>UN9</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=UN9:N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)CARBONYL]GLYCINE'>UN9</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ABH5, ALKBH5, OFOXD1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4nj4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nj4 OCA], [https://pdbe.org/4nj4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nj4 RCSB], [https://www.ebi.ac.uk/pdbsum/4nj4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nj4 ProSAT]</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=4nj4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nj4 OCA], [http://pdbe.org/4nj4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4nj4 RCSB], [http://www.ebi.ac.uk/pdbsum/4nj4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4nj4 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/ALKB5_HUMAN ALKB5_HUMAN]] Dioxygenase that demethylates RNA by oxidative demethylation: specifically demethylates N(6)-methyladenosine (m(6)A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Requires molecular oxygen, alpha-ketoglutarate and iron. Demethylation of m(6)A mRNA affects mRNA processing and export and is required for spermatogenesis.<ref>PMID:21264265</ref> <ref>PMID:23177736</ref>
+[https://www.uniprot.org/uniprot/ALKB5_HUMAN ALKB5_HUMAN] Dioxygenase that demethylates RNA by oxidative demethylation: specifically demethylates N(6)-methyladenosine (m(6)A) RNA, the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Requires molecular oxygen, alpha-ketoglutarate and iron. Demethylation of m(6)A mRNA affects mRNA processing and export and is required for spermatogenesis.<ref>PMID:21264265</ref> <ref>PMID:23177736</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 20: @@
 ==See Also==
-*[[Dioxygenase|Dioxygenase]]
+*[[Dioxygenase 3D structures|Dioxygenase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Aik, W S]]
+[[Category: Large Structures]]
-[[Category: McDonough, M A]]
+[[Category: Aik WS]]
-[[Category: Schofield, C J]]
+[[Category: McDonough MA]]
-[[Category: Dioxygenase]]
+[[Category: Schofield CJ]]
-[[Category: Double-stranded beta helix]]
-[[Category: Jelly-roll motif]]
-[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
-[[Category: Rna]]
-[[Category: Rna demethylase]]

4nj4

From Proteopedia

Revision as of 08:30, 11 January 2023

Crystal Structure of Human ALKBH5

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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