A polypeptide having the activity of inhibiting the dimethylation of histone methylase dot1l, an inhibitor and its design method and application
A technology of methylase and dimethylation, applied in chemical instruments and methods, peptide/protein components, medical preparations containing active ingredients, etc., can solve the problems of indistinguishable inhibition, etc., and achieve good application prospects, good Inhibitory effect, strong specific effect
Active Publication Date: 2021-07-27
THE FIFTH AFFILIATED HOSPITAL SUN YAT SEN UNIV
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Problems solved by technology
[0007] At present, EPZ-5676, a small-molecule drug that inhibits the active center of Dot1L designed based on protein structure information, has entered the second clinical trial in the United States, but because the small molecule cannot distinguish between monomethylation, dimethylation and There are three enzyme activity reactions of trimethylation, so it is urgent to study the structural characteristics of various enzyme activity regulators of Dot1L, and find a substance that can specifically inhibit the dimethylation activity of this enzyme
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Embodiment 1
[0070] Embodiment 1 of the present invention is: a method for designing a polypeptide having the activity of inhibiting the dimethylation of histone methylase DOT1L, comprising the following steps:
[0071] 1. By means of molecular biology techniques such as molecular cloning and Escherichia coli prokaryotic expression system based on secondary structure prediction, co-expression or separate expression of the interaction segment of interest in the complex, through co-expression or co-purification The protein complex of the AF10-Dot1L interaction segment was obtained by the method, and the crystal structure of the complex is as follows figure 1 As shown, the in vivo protein complementation experiment, phage display and yeast two-hybrid experimental system were established to identify the precursor of the polypeptide molecule that specifically binds to AF10.
[0072] 2. Screen and optimize the crystal growth conditions of the AF10-Dot1L complex by means of crystallography experi...
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The invention discloses a polypeptide having the activity of inhibiting the dimethylation of histone methylase DOT1L, an inhibitor and a design method and application thereof. The amino acid sequence of the polypeptide is shown in Seq No.1. Such inhibitors include the polypeptides described above. The design method includes the following steps: S1, obtaining the crystal structure of the AF10-DOT1L complex, and finding out a polypeptide precursor capable of inhibiting DOT1L binding; S2, obtaining the AF10-polypeptide precursor complex crystal; S4, on the basis of S3, further optimize the polypeptide with the activity of inhibiting the dimethylation of histone methylase DOT1L. The present invention also includes the application of the above polypeptide in the preparation of histone demethylase DOT1L inhibitor drugs. Compared with the prior art, the polypeptide can specifically inhibit the dimethylation activity of histone methylase DOT1L, and has good application prospects.
Description
technical field [0001] The invention relates to the technical field of biomedical engineering, in particular to a polypeptide having the activity of inhibiting the dimethylation of histone methylase DOT1L, an inhibitor, a design method and application thereof. Background technique [0002] Epigenetics is a discipline that gradually emerged in the 1980s. It was gradually developed in the process of studying many life phenomena that do not conform to the inheritance rules of classic Mendelian genetics. The main research content of epigenetics roughly includes two aspects: 1) the regulation of gene selective transcription and expression, specifically including DNA methylation, gene imprinting, histone covalent modification and chromatin remodeling; 2) gene post-transcriptional regulation, including non-coding RNAs, microRNAs, antisense RNAs, introns, and riboswitches in the genome. The basic unit of chromatin is the nucleosome, which is composed of DNA and histones. The struc...
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IPC IPC(8): C07K14/00A61K38/16A61P35/00
CPCA61K38/00A61P35/00C07K14/00
Inventor 陈守登黄钊霞康斯斯周子亮陈小雪
Owner THE FIFTH AFFILIATED HOSPITAL SUN YAT SEN UNIV