Home
Database
Research
About us
Mixed lineage leukemia proteins (MLL) aptermer
Timeline
Show that MLL regulates target Hox gene expression through direct binding to promoter sequences. We further show that the MLL SET domain is a histone H3 lysine 4-specific methyltransferase whose activity is stimulated with acetylated H3 peptides[1]
Report that MLL is normally cleaved at two conserved sites (D/GADD and D/GVDD) and that mutation of these sites abolishes the proteolysis. MLL cleavage generates N-terminal p320 (N320) and C-terminal p180 (C180) fragments, which form a stable complex that localizes to a subnuclear compartment[2]
The crystal structure of the MLL1 SET domain in complex with cofactor product AdoHcy and a histone H3 peptide were determined[7]
Designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon -CO-ARA-NH-, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with K(i) < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay[9]
Report a comprehensive characterization of our recently developed inhibitor MM-401 that targets the MLL1 H3K4 methyltransferase activity[10]
Description
In 2008, Southall, S.M. and his colleagues determined the crystal structure of the MLL1 SET domain in complex with cofactor product AdoHcy and a histone H3 peptide. In 2019, Ul-Haq and his colleagues screened and isolated MLL1-binding ssRNAs using SELEX (Systemic Evolution of Ligands by Exponential enrichment) technology[9,11].SELEX
In 2019, Ul-Haq and his colleagues screened and isolated MLL1-binding ssRNAs using SELEX (Systemic Evolution of Ligands by Exponential enrichment)[11].
Detailed information are accessible on SELEX page.
Structure
The 2D structure of the figure is based on the article by ribodraw tool to draw[11].5'-GGCUCGAGGAACGUACAGAGGGUGGAGAGUGGGUGGAAGCUUACGGUACCUAGC-3'
Ligand information
SELEX ligand
The myeloid/lymphoid or mixed lineage leukemia proteins (MLLs) are the key histone lysine methyltransferases (HKMTs) that regulate the expression of a number of genes, including homeobox (HOX) gene, thereby affecting hematopoiesis and development in mammals.-----from article
| Name | Uniprot ID | Pfam | MW | Amino acids sequences | PDB | Gene ID |
|---|---|---|---|---|---|---|
| Mixed lineage leukemia proteins (MLL) | A7RZU9 | A0A068YNS4 | 110.563 kDa | MKEMVGGCCVCSDERGWAENPLVYCDGHACSVAVHQACYGIVQVPTGPWFCRKCESQERAARVRCELCPHKDGALKRTDNGGWAHVVCALYIPEVQFANVLTMEPIVLQYVPHDRFNKTCYICEEQGRESKAASGACMTCNRHGCRQAFHVTCAQMAGLLCEEEVLEVDNVKYCGYCKYHFSKMKTSRHSSGGGGGAGGGSSGGGGGGSSSASGGGGGTGGGSGNSFLSGRRSRSASPSTQPEKHPTHHEKGQKKSRKDKERLKQKHKKRPESPPSVLAPPAVPTADKVSSATSSSHHEASTQETSESSRDSKGRKSSSHSLSHKDKKLGTGKGSSLQSSPDFAAFPKLEQPEEDKYPKPADPTPPAPPSPTAPEPPKADLFEQKVVFSGFGPIMRFTTTASSSSRARAPSPGDYKSPHITGAGASAGTHKRMPALSATLGPAEEAPETTLKEKKHKASKRSRHGPGRPKGSRGKEGASGPTASLPAAQLAGFTATAASPFSGGSLVSAGLGGLASRTFGPSGSLPSLSLESSLLGAGIYTSNKDPISHGGGMLRAVCSTPLSSSLLGPTGTSALPRLSRSPFTSTLASSSASISTTQVFSLAGSTFSLPSSHIFGTPMGTVNPLLTQAESSHTEPDLEDCSFRCHGTSPQESLSSMSPISSLPALFDQTSAPCAGGQLDSTAPGTTNMEQLLEKQGDGEAGVNIVEMLKALHALQKENQRLQEQILSLTAKKERLQVLNVQLSVPFPALPAALPATNGPIPGPYGLLPQAGSSDSLSVSKSPPGKNSLGLDNSLSTSSEDPHSGCPSRSSSSLSFHSTPPPLPLLQQSPATLPLALPGAPAPLPPQPQNGLGRAPGATGLGAMPMAEGLLGGLAGSGSLPLNGLLGGLNGAAAPNPAGLSQAGGAPTLQLPGCLNSLTEQQRHLLQQQEQQLQQLQQLLASPQLTPEHQTVVYQMIQQMQQKRELQRLQMAGGSQLPMASLLAGSSTPLLSAGTPGLLPTASAPPLLPAGALVAPSLGSNTSLMAAAAAAAAVAAAGGPPVLTAQTNPFLSLPGADASGNGPKGGTADKGASTSQEKG | 3RE2 | V00642 |
Some isolated sequences bind to the affinity of the protein.
| Name | Sequence | Ligand | Affinity |
|---|---|---|---|
| APT 1 | 5'-GGCUCGAGGAACGUACAGAGGGUGGAGAGUGGGUGGAAGCUUACGGUACCUAGC-3' | Mixed lineage leukemia protein 1 (MLL1) | NA |
| APT 2 | 5'-GGCUCGAGGACGUAACAGAGGGAGGCGAGUGGGUGGAAGCUUACGGUACCUAGC-3' | Mixed lineage leukemia protein 1 (MLL1) | NA |
Similar compound
We used the Dail server website to compare the structural similarities of ligand proteins, and chose the top 10 in terms of similarity for presentation. The Dali server is a network service for comparing protein structures in 3D. Dali compares them against those in the Protein Data Bank (PDB). Z-score is a standard score that is converted from an original score. The list of neighbours is sorted by Z-score. Similarities with a Z-score lower than 2 are spurious. RMSD(Root Mean Square Deviation) value is used to measure the degree to which atoms deviate from the alignment position.
| Named | CAS | Pubchem CID | Structure |
|---|---|---|---|
| 3U84-A | 45.9 | 429 | Menin |
| 5A6C-B | 8.3 | 197 | G-protein-signaling modulator 2, afadin |
| 4HOR-A | 8.2 | 191 | Interferon-induced protein with tetratricopept |
| 7KTR-A | 7.9 | 222 | Transformation/transcription domain-associated |
| 5O01-A | 7.9 | 161 | Bklc (bacterial kinesin-light chain-like) |
| 3GW4-B | 7.8 | 150 | Uncharacterized protein |
| 8G53-A | 7.8 | 151 | Tpr_region domain-containing protein |
| 5AN3-B | 7.8 | 123 | Sgt1 |
| 4FGP-A | 7.8 | 132 | Periplasmic protein |
| 2QFC-A | 7.6 | 172 | Plcr protein |
References
[1] MLL targets SET domain methyltransferase activity to Hox gene promoters.Milne, T. A., Briggs, S. D., Brock, H. W., Martin, M. E., Gibbs, D., Allis, C. D., & Hess, J. L.
Mol. Cell, 10, 1107-1117. (2002)
[2] Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization.
Hsieh, J. J., Ernst, P., Erdjument-Bromage, H., Tempst, P., & Korsmeyer, S. J.
Mol. Cell. Biol., 23, 186-194. (2003)
[3] MLL associates specifically with a subset of transcriptionally active target genes.
Milne, T. A., Dou, Y., Martin, M. E., Brock, H. W., Roeder, R. G., & Hess, J. L.
Proceedings of the National Academy of Sciences of the United States of America, 102(41), 14765–14770. (2005)
[4] Dynamic lysine methylation on histone H3 defines the regulatory phase of gene transcription.
Morillon, A., Karabetsou, N., Nair, A., & Mellor, J.
Mol. Cell, 18, 723-734. (2005)
[5] Mechanisms of transcriptional regulation by MLL and its disruption in acute leukemia.
Dou, Y., & Hess, J. L.
International journal of hematology, 87(1), 10–18. (2008)
[6] Regulation of MLL1 H3K4 methyltransferase activity by its core components.
Dou, Y., Milne, T. A., Ruthenburg, A. J., Lee, S., Lee, J. W., Verdine, G. L., Allis, C. D., & Roeder, R. G.
Nat. Struct. Mol. Biol., 13, 713-719. (2008)
[7] Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks.
Southall, S. M., Wong, P. S., Odho, Z., Roe, S. M., & Wilson, J. R.
Mol. Cell, 33, 181-191. (2009)
[8] Establishment of active chromatin structure at enhancer elements by mixed-lineage leukemia 1 to initiate estrogendependent gene expression. Nucleic Acids Res., 42, 2245-2256.
Jeong, K. W., Andreu-Vieyra, C., You, J. S., Jones, P. A., & Stallcup, M. R.
Nucleic Acids Res., 42, 2245-2256. (2013)
[9] High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.
Karatas, H., Townsend, E. C., Cao, F., Chen, Y., Bernard, D., Liu, L., Lei, M., Dou, Y., & Wang, S.
Journal of the American Chemical Society, 135(2) (2013)
[10] Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia.
Cao, F., Townsend, E. C., Karatas, H., Xu, J., Li, L., Lee, S., Liu, L., Chen, Y., Ouillette, P., Zhu, J., Hess, J. L., Atadja, P., Lei, M., Qin, Z. S., Malek, S., Wang, S., & Dou, Y.
Molecular cell, 53(2), 247–261. (2014)
[11] Isolation of MLL1 Inhibitory RNA Aptamers.
Ul-Haq, A., Jin, M. L., Jeong, K. W., Kim, H. M., & Chun, K. H.
Biomolecules & therapeutics, 27(2), 201–209. (2019)