9jur
Crystal Structure of NHL domain of human E3 ubiquitin-protein ligase TRIM71
Structural highlights
DiseaseLIN41_HUMAN Congenital communicating hydrocephalus. The disease is caused by variants affecting the gene represented in this entry. FunctionLIN41_HUMAN E3 ubiquitin-protein ligase that cooperates with the microRNAs (miRNAs) machinery and promotes embryonic stem cells proliferation and maintenance (Probable). Binds to miRNAs and associates with AGO2, participating in post-transcriptional repression of transcripts such as CDKN1A (By similarity). In addition, participates in post-transcriptional mRNA repression in a miRNA independent mechanism (PubMed:23125361). Facilitates the G1-S transition to promote rapid embryonic stem cell self-renewal by repressing CDKN1A expression. Required to maintain proliferation and prevent premature differentiation of neural progenitor cells during early neural development: positively regulates FGF signaling by controlling the stability of SHCBP1 (By similarity). Specific regulator of miRNA biogenesis. Binds to miRNA MIR29A hairpin and postranscriptionally modulates MIR29A levels, which indirectly regulates TET proteins expression (PubMed:28431233).[UniProtKB:Q1PSW8][1] [2] [3] Publication Abstract from PubMedTRIM71 NHL Domain is a critical driver of various cellular process and is dysregulated in several medical conditions like non-small cell lung cancer, hepatocellular carcinoma and congenital hydrocephalus. However, its pathways and binding with CDKN1A has not been well studied. To investigate its interaction with CDKN1A, we expressed TRIM71 NHL domain in SF9 (Spodoptera frugiperda) insect cells using the pFastBacTM HT B plasmid, was purified by size exclusion chromatography and its crystal structure was determined successfully (PDB ID: 9JUR). Fluorescence polarization (Kd = 0.42 +/- 0.04 muM) and EMSA confirmed strong and specific binding to CDKN1A mRNA, indicating its role in repressing CDKN1A expression to promote cancer cell proliferation. To further delve into its therapeutic implication, we screened a library of 2517 phytochemicals from 48 medicinal plants to identify potential natural inhibitors of the TRIM71 NHL domain. Epigallocatechin Gallate and Cyanidin 3-O-galactoside demonstrated binding affinities of -9.1 kcal/mol and -9.0 kcal/mol, respectively, while SPR confirmed their affinities with Kd values of 3.2 muM and 17.3 muM, accordingly. Molecular dynamics simulations confirmed protein-ligand complexes stability. In summary, human TRIM71 NHL domain crystal structure provides a foundation for understanding its structural features while exploring two potential inhibitors for therapeutic applications. Human tripartite motif-containing protein 71 NCL-1/HT2A/LIN-41 domain crystal structure and its potential natural inhibitors.,Lin L, Hasan MKE, Gu X, Khan SU, Hossain A, Faruqe MO, Shahriar S, Joy MNH, Sourov MMH, Khan MI, Zhang L, Lv M, Shi Y Int J Biol Macromol. 2025 Apr 1;309(Pt 3):142764. doi: , 10.1016/j.ijbiomac.2025.142764. PMID:40180090[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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