9vpq

Crystal structure of METTL9 in complex with compound 15k

Structural highlights

9vpq 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 2.28Å
Ligands:	A1ES7
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

METL9_HUMAN Protein-histidine N-methyltransferase that specifically catalyzes 1-methylhistidine (pros-methylhistidine) methylation of target proteins (PubMed:33563959, PubMed:34562450, PubMed:37015930, PubMed:37398635). Specifically methylates the second His of proteins with a His-x-His (HxH) motif (where 'x' is preferably a small amino acid), while exploiting the first one as a recognition signature (PubMed:37398635). Catalyzes methylation of target proteins such as S100A9, NDUFB3, SLC39A5, SLC39A7, ARMC6 and DNAJB12; 1-methylhistidine modification may affect the binding of zinc and other metals to its target proteins (PubMed:33563959, PubMed:34562450, PubMed:37015930, PubMed:37398635). Constitutes the main methyltransferase for the 1-methylhistidine modification in cell (PubMed:33563959).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Protein histidine N1-methylation (1-methylhistidine, 1-MH) is a prevalent yet underexplored post-translational modification in mammals. The methyltransferase METTL9 acts as an important enzyme catalyzing 1-MH of histidine in diverse protein substrates, with mounting evidence suggesting its involvement in tumor progression. Despite its potential significance, no inhibitors targeting METTL9 have been previously identified. Here, we introduce compound METTL9i as a first-in-class, highly potent, and selective METTL9 inhibitor. METTL9i inhibits METTL9 with a half-maximum inhibitory concentration (IC(50)) of 0.067 +/- 0.009 microM and exhibits selectivity over other methyltransferases. Structural analysis via crystallography reveals that METTL9i binds within the S-adenosylmethionine (SAM) binding pocket. In cells, METTL9i engages METTL9 and leads to a reduction in global 1-MH levels. These results support METTL9i as a useful tool compound for investigating METTL9 biology and the functions of histidine 1-MH, while also serving as a promising lead compound for drug discovery targeting METTL9.

Discovery of a Potent and Selective Cell-Active Inhibitor of Histidine-N1 Methyltransferase METTL9.,Yao R, Zhang G, Huang Y, Fan D, Zhang H, Qiao J, Chen C, Shao Z, Li L, Yang S Angew Chem Int Ed Engl. 2026 Mar 23:e3642560. doi: 10.1002/anie.3642560. PMID:41870122^[5]

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

References

↑ Davydova E, Shimazu T, Schuhmacher MK, Jakobsson ME, Willemen HLDM, Liu T, Moen A, Ho AYY, Małecki J, Schroer L, Pinto R, Suzuki T, Grønsberg IA, Sohtome Y, Akakabe M, Weirich S, Kikuchi M, Olsen JV, Dohmae N, Umehara T, Sodeoka M, Siino V, McDonough MA, Eijkelkamp N, Schofield CJ, Jeltsch A, Shinkai Y, Falnes PØ. The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes. Nat Commun. 2021 Feb 9;12(1):891. PMID:33563959 doi:10.1038/s41467-020-20670-7
↑ Daitoku H, Someya M, Kako K, Hayashi T, Tajima T, Haruki H, Sekiguchi N, Uetake T, Akimoto Y, Fukamizu A. siRNA screening identifies METTL9 as a histidine Nπ-methyltransferase that targets the proinflammatory protein S100A9. J Biol Chem. 2021 Nov;297(5):101230. PMID:34562450 doi:10.1016/j.jbc.2021.101230
↑ Wang X, Xie H, Guo Q, Cao D, Ru W, Zhao S, Zhu Z, Zhang J, Pan W, Yao X, Xu C. Molecular basis for METTL9-mediated N1-histidine methylation. Cell Discov. 2023 Apr 4;9(1):38. PMID:37015930 doi:10.1038/s41421-023-00548-w
↑ Zhao W, Zhou Y, Li C, Bi Y, Wang K, Ye M, Li H. Molecular basis for protein histidine N1-specific methylation of the "His-x-His" motifs by METTL9. Cell Insight. 2023 Mar 31;2(3):100090. PMID:37398635 doi:10.1016/j.cellin.2023.100090
↑ Yao R, Zhang G, Huang Y, Fan D, Zhang H, Qiao J, Chen C, Shao Z, Li L, Yang S. Discovery of a Potent and Selective Cell-Active Inhibitor of Histidine-N1 Methyltransferase METTL9. Angew Chem Int Ed Engl. 2026 Mar 23:e3642560. PMID:41870122 doi:10.1002/anie.3642560

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Davydova E, Shimazu T, Schuhmacher MK, Jakobsson ME, Willemen HLDM, Liu T, Moen A, Ho AYY, Małecki J, Schroer L, Pinto R, Suzuki T, Grønsberg IA, Sohtome Y, Akakabe M, Weirich S, Kikuchi M, Olsen JV, Dohmae N, Umehara T, Sodeoka M, Siino V, McDonough MA, Eijkelkamp N, Schofield CJ, Jeltsch A, Shinkai Y, Falnes PØ. The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes. Nat Commun. 2021 Feb 9;12(1):891. PMID:33563959 doi:10.1038/s41467-020-20670-7

[2] Daitoku H, Someya M, Kako K, Hayashi T, Tajima T, Haruki H, Sekiguchi N, Uetake T, Akimoto Y, Fukamizu A. siRNA screening identifies METTL9 as a histidine Nπ-methyltransferase that targets the proinflammatory protein S100A9. J Biol Chem. 2021 Nov;297(5):101230. PMID:34562450 doi:10.1016/j.jbc.2021.101230

[3] Wang X, Xie H, Guo Q, Cao D, Ru W, Zhao S, Zhu Z, Zhang J, Pan W, Yao X, Xu C. Molecular basis for METTL9-mediated N1-histidine methylation. Cell Discov. 2023 Apr 4;9(1):38. PMID:37015930 doi:10.1038/s41421-023-00548-w

[4] Zhao W, Zhou Y, Li C, Bi Y, Wang K, Ye M, Li H. Molecular basis for protein histidine N1-specific methylation of the "His-x-His" motifs by METTL9. Cell Insight. 2023 Mar 31;2(3):100090. PMID:37398635 doi:10.1016/j.cellin.2023.100090

[5] Yao R, Zhang G, Huang Y, Fan D, Zhang H, Qiao J, Chen C, Shao Z, Li L, Yang S. Discovery of a Potent and Selective Cell-Active Inhibitor of Histidine-N1 Methyltransferase METTL9. Angew Chem Int Ed Engl. 2026 Mar 23:e3642560. PMID:41870122 doi:10.1002/anie.3642560

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9vpq

Crystal structure of METTL9 in complex with compound 15k

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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