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<StructureSection load='6ttp' size='340' side='right'caption='[[6ttp]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='6ttp' size='340' side='right'caption='[[6ttp]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6ttp]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TTP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6TTP FirstGlance]. <br>
<table><tr><td colspan='2'>[[6ttp]] 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=6TTP OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6TTP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ADN:ADENOSINE'>ADN</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ADN:ADENOSINE'>ADN</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">METTL3, MTA70 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), METTL14, KIAA1627 ([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/mRNA_m(6)A_methyltransferase mRNA m(6)A methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.348 2.1.1.348] </span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/mRNA_m(6)A_methyltransferase mRNA m(6)A methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.348 2.1.1.348] </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=6ttp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ttp OCA], [http://pdbe.org/6ttp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ttp RCSB], [http://www.ebi.ac.uk/pdbsum/6ttp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ttp ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6ttp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ttp OCA], [http://pdbe.org/6ttp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ttp RCSB], [http://www.ebi.ac.uk/pdbsum/6ttp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ttp ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/MTA70_HUMAN MTA70_HUMAN]] N6-methyltransferase that methylates adenosine residues of some RNAs and acts as a regulator of the circadian clock, differentiation of embryonic stem cells and primary miRNA processing. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing, translation efficiency, editing and mRNA stability (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:9409616). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998).[UniProtKB:Q8C3P7]<ref>PMID:22575960</ref> <ref>PMID:24284625</ref> <ref>PMID:25719671</ref> <ref>PMID:25799998</ref> <ref>PMID:26321680</ref> <ref>PMID:26593424</ref> <ref>PMID:9409616</ref>  [[http://www.uniprot.org/uniprot/MET14_HUMAN MET14_HUMAN]] N6-methyltransferase that methylates adenosine residues of some mRNAs and acts as a regulator of the circadian clock and differentiation of embryonic stem cells. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing and mRNA stability (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop. M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization (By similarity).[UniProtKB:Q3UIK4]<ref>PMID:24316715</ref> <ref>PMID:24407421</ref> <ref>PMID:25719671</ref>   
[[http://www.uniprot.org/uniprot/MTA70_HUMAN MTA70_HUMAN]] N6-methyltransferase that methylates adenosine residues of some RNAs and acts as a regulator of the circadian clock, differentiation of embryonic stem cells and primary miRNA processing. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing, translation efficiency, editing and mRNA stability (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:9409616). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998).[UniProtKB:Q8C3P7]<ref>PMID:22575960</ref> <ref>PMID:24284625</ref> <ref>PMID:25719671</ref> <ref>PMID:25799998</ref> <ref>PMID:26321680</ref> <ref>PMID:26593424</ref> <ref>PMID:9409616</ref>  [[http://www.uniprot.org/uniprot/MET14_HUMAN MET14_HUMAN]] N6-methyltransferase that methylates adenosine residues of some mRNAs and acts as a regulator of the circadian clock and differentiation of embryonic stem cells. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing and mRNA stability (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop. M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization (By similarity).[UniProtKB:Q3UIK4]<ref>PMID:24316715</ref> <ref>PMID:24407421</ref> <ref>PMID:25719671</ref>   
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The RNA methylase METTL3 catalyzes the transfer of a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to the N(6) atom of adenine. We have screened a library of 4000 analogues and derivatives of the adenosine moiety of SAM by high-throughput docking into METTL3. Two series of adenine derivatives were identified in silico, and the binding mode of six of the predicted inhibitors was validated by protein crystallography. Two compounds, one for each series, show good ligand efficiency. We propose a route for their further development into potent and selective inhibitors of METTL3.
Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer.,Bedi RK, Huang D, Eberle SA, Wiedmer L, Sledz P, Caflisch A ChemMedChem. 2020 May 6;15(9):744-748. doi: 10.1002/cmdc.202000011. Epub 2020 Mar, 23. PMID:32159918<ref>PMID:32159918</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ttp" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Bedi, R K]]
[[Category: Bedi, R K]]

Revision as of 13:10, 16 September 2020

Crystal structure of the human METTL3-METTL14 complex bound to Compound 1/Adenosine (DHU_M3M_023)Crystal structure of the human METTL3-METTL14 complex bound to Compound 1/Adenosine (DHU_M3M_023)

Structural highlights

6ttp is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:METTL3, MTA70 (HUMAN), METTL14, KIAA1627 (HUMAN)
Activity:mRNA m(6)A methyltransferase, with EC number 2.1.1.348
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[MTA70_HUMAN] N6-methyltransferase that methylates adenosine residues of some RNAs and acts as a regulator of the circadian clock, differentiation of embryonic stem cells and primary miRNA processing. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing, translation efficiency, editing and mRNA stability (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:9409616). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998).[UniProtKB:Q8C3P7][1] [2] [3] [4] [5] [6] [7] [MET14_HUMAN] N6-methyltransferase that methylates adenosine residues of some mRNAs and acts as a regulator of the circadian clock and differentiation of embryonic stem cells. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing and mRNA stability (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop. M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization (By similarity).[UniProtKB:Q3UIK4][8] [9] [10]

Publication Abstract from PubMed

The RNA methylase METTL3 catalyzes the transfer of a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to the N(6) atom of adenine. We have screened a library of 4000 analogues and derivatives of the adenosine moiety of SAM by high-throughput docking into METTL3. Two series of adenine derivatives were identified in silico, and the binding mode of six of the predicted inhibitors was validated by protein crystallography. Two compounds, one for each series, show good ligand efficiency. We propose a route for their further development into potent and selective inhibitors of METTL3.

Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer.,Bedi RK, Huang D, Eberle SA, Wiedmer L, Sledz P, Caflisch A ChemMedChem. 2020 May 6;15(9):744-748. doi: 10.1002/cmdc.202000011. Epub 2020 Mar, 23. PMID:32159918[11]

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

References

  1. ↑ Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012 Apr 29;485(7397):201-6. doi: 10.1038/nature11112. PMID:22575960 doi:http://dx.doi.org/10.1038/nature11112
  2. ↑ Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014 Jan 2;505(7481):117-20. doi: 10.1038/nature12730. Epub 2013 Nov 27. PMID:24284625 doi:http://dx.doi.org/10.1038/nature12730
  3. ↑ Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015 Feb 26;518(7540):560-4. doi: 10.1038/nature14234. PMID:25719671 doi:http://dx.doi.org/10.1038/nature14234
  4. ↑ Alarcon CR, Lee H, Goodarzi H, Halberg N, Tavazoie SF. N6-methyladenosine marks primary microRNAs for processing. Nature. 2015 Mar 26;519(7544):482-5. doi: 10.1038/nature14281. Epub 2015 Mar 18. PMID:25799998 doi:http://dx.doi.org/10.1038/nature14281
  5. ↑ Alarcon CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events. Cell. 2015 Sep 10;162(6):1299-308. doi: 10.1016/j.cell.2015.08.011. Epub 2015 Aug, 27. PMID:26321680 doi:http://dx.doi.org/10.1016/j.cell.2015.08.011
  6. ↑ Meyer KD, Patil DP, Zhou J, Zinoviev A, Skabkin MA, Elemento O, Pestova TV, Qian SB, Jaffrey SR. 5' UTR m(6)A Promotes Cap-Independent Translation. Cell. 2015 Nov 5;163(4):999-1010. doi: 10.1016/j.cell.2015.10.012. Epub 2015 Oct , 22. PMID:26593424 doi:http://dx.doi.org/10.1016/j.cell.2015.10.012
  7. ↑ Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA. 1997 Nov;3(11):1233-47. PMID:9409616
  8. ↑ Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, Dai Q, Chen W, He C. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014 Feb;10(2):93-5. doi: 10.1038/nchembio.1432. Epub 2013 Dec 6. PMID:24316715 doi:http://dx.doi.org/10.1038/nchembio.1432
  9. ↑ Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, Zhao YL, Wang X, Rendtlew Danielsen JM, Liu F, Yang YG. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014 Feb;24(2):177-89. doi: 10.1038/cr.2014.3. Epub 2014 Jan 10. PMID:24407421 doi:http://dx.doi.org/10.1038/cr.2014.3
  10. ↑ Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015 Feb 26;518(7540):560-4. doi: 10.1038/nature14234. PMID:25719671 doi:http://dx.doi.org/10.1038/nature14234
  11. ↑ Bedi RK, Huang D, Eberle SA, Wiedmer L, Sledz P, Caflisch A. Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer. ChemMedChem. 2020 May 6;15(9):744-748. doi: 10.1002/cmdc.202000011. Epub 2020 Mar, 23. PMID:32159918 doi:http://dx.doi.org/10.1002/cmdc.202000011

6ttp, resolution 2.00Å

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