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4nro

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Revision as of 08:35, 18 January 2023

Crystal structure of human ALKBH5 in complex with alpha-ketoglutarate

Structural highlights

4nro is a 1 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

N(6)-Methylation of adenosine is the most ubiquitous and abundant modification of nucleoside in eukaryotic mRNA and long non-coding RNA. This modification plays an essential role in the regulation of mRNA translation and RNA metabolism. Recently, human AlkB homolog 5 (Alkbh5) and fat mass- and obesity-associated protein (FTO) were shown to erase this methyl modification on mRNA. Here, we report five high resolution crystal structures of the catalytic core of Alkbh5 in complex with different ligands. Compared with other AlkB proteins, Alkbh5 displays several unique structural features on top of the conserved double-stranded beta-helix fold typical of this protein family. Among the unique features, a distinct "lid" region of Alkbh5 plays a vital role in substrate recognition and catalysis. An unexpected disulfide bond between Cys-230 and Cys-267 is crucial for the selective binding of Alkbh5 to single-stranded RNA/DNA by bringing a "flipping" motif toward the central beta-helix fold. We generated a substrate binding model of Alkbh5 based on a demethylation activity assay of several structure-guided site-directed mutants. Crystallographic and biochemical studies using various analogs of alpha-ketoglutarate revealed that the active site cavity of Alkbh5 is much smaller than that of FTO and preferentially binds small molecule inhibitors. Taken together, our findings provide a structural basis for understanding the substrate recognition specificity of Alkbh5 and offer a foundation for selective drug design against AlkB members.

Crystal structures of the human RNA demethylase Alkbh5 reveal basis for substrate recognition.,Feng C, Liu Y, Wang G, Deng Z, Zhang Q, Wu W, Tong Y, Cheng C, Chen Z J Biol Chem. 2014 Apr 25;289(17):11571-83. doi: 10.1074/jbc.M113.546168. Epub, 2014 Mar 10. PMID:24616105^[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
↑ Feng C, Liu Y, Wang G, Deng Z, Zhang Q, Wu W, Tong Y, Cheng C, Chen Z. Crystal structures of the human RNA demethylase Alkbh5 reveal basis for substrate recognition. J Biol Chem. 2014 Apr 25;289(17):11571-83. doi: 10.1074/jbc.M113.546168. Epub, 2014 Mar 10. PMID:24616105 doi:http://dx.doi.org/10.1074/jbc.M113.546168

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/4nro"

Categories: Homo sapiens | Large Structures | Chen Z | Feng C | Liu Y

@@ Line 1: / Line 1: @@
 ==Crystal structure of human ALKBH5 in complex with alpha-ketoglutarate==
-<StructureSection load='4nro' size='340' side='right' caption='[[4nro]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='4nro' size='340' side='right'caption='[[4nro]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4nro]] is a 1 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=4NRO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NRO FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4nro]] is a 1 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=4NRO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NRO FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4nrm|4nrm]], [[4nrp|4nrp]], [[4nrq|4nrq]]</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=4nro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nro OCA], [https://pdbe.org/4nro PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nro RCSB], [https://www.ebi.ac.uk/pdbsum/4nro PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nro ProSAT]</span></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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4nro FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nro OCA], [http://pdbe.org/4nro PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4nro RCSB], [http://www.ebi.ac.uk/pdbsum/4nro PDBsum]</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: Chen, Z]]
+[[Category: Large Structures]]
-[[Category: Feng, C]]
+[[Category: Chen Z]]
-[[Category: Liu, Y]]
+[[Category: Feng C]]
-[[Category: 6-methyl adenosine]]
+[[Category: Liu Y]]
-[[Category: Alkbh5]]
-[[Category: Demethylation]]
-[[Category: Human dioxygenase]]
-[[Category: Metal-binding]]
-[[Category: Nucleus]]
-[[Category: Oxidoreductase]]
-[[Category: Protein/dna interaction]]
-[[Category: Rna repair]]

4nro

From Proteopedia

Revision as of 08:35, 18 January 2023

Crystal structure of human ALKBH5 in complex with alpha-ketoglutarate

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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