6mgn
From Proteopedia
mouse Id1 (51-104) - human hE47 (348-399) complex
Structural highlights
Disease[TFE2_HUMAN] Precursor B-cell acute lymphoblastic leukemia. Chromosomal aberrations involving TCF3 are cause of forms of pre-B-cell acute lymphoblastic leukemia (B-ALL). Translocation t(1;19)(q23;p13.3) with PBX1. TCF3-PBX1 transforms cells by constitutively activating transcription of genes regulated by PBX1 or by other members of the PBX protein family. Translocation t(17;19)(q22;p13.3) with HLF. Inversion inv(19)(p13;q13) with TFPT. Function[TFE2_HUMAN] Transcriptional regulator. Involved in the initiation of neuronal differentiation. Heterodimers between TCF3 and tissue-specific basic helix-loop-helix (bHLH) proteins play major roles in determining tissue-specific cell fate during embryogenesis, like muscle or early B-cell differentiation. Dimers bind DNA on E-box motifs: 5'-CANNTG-3'. Binds to the kappa-E2 site in the kappa immunoglobulin gene enhancer. Binds to IEB1 and IEB2, which are short DNA sequences in the insulin gene transcription control region. [ID1_MOUSE] Transcriptional regulator (lacking a basic DNA binding domain) which negatively regulates the basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibiting their DNA binding and transcriptional activity. Implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, apoptosis, angiogenesis, and neoplastic transformation. Inhibits skeletal muscle and cardiac myocyte differentiation. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-ARNTL/BMAL1 heterodimer.[1] [2] Publication Abstract from PubMedId helix-loop-helix (HLH) proteins (Id1-4) bind E protein bHLH transcription factors, preventing them from forming active transcription complexes that drive changes in cell states. Id proteins are primarily expressed during development to inhibit differentiation, but they become re-expressed in adult tissues in diseases of the vasculature and cancer. We show that the genetic loss of Id1/Id3 reduces ocular neovascularization in mouse models of wet age-related macular degeneration (AMD) and retinopathy of prematurity (ROP). An in silico screen identifies AGX51, a small-molecule Id antagonist. AGX51 inhibits the Id1-E47 interaction, leading to ubiquitin-mediated degradation of Ids, cell growth arrest, and reduced viability. AGX51 is well-tolerated in mice and phenocopies the genetic loss of Id expression in AMD and ROP models by inhibiting retinal neovascularization. Thus, AGX51 is a first-in-class compound that antagonizes an interaction formerly considered undruggable and that may have utility in the management of multiple diseases. A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization.,Wojnarowicz PM, Lima E Silva R, Ohnaka M, Lee SB, Chin Y, Kulukian A, Chang SH, Desai B, Garcia Escolano M, Shah R, Garcia-Cao M, Xu S, Kadam R, Goldgur Y, Miller MA, Ouerfelli O, Yang G, Arakawa T, Albanese SK, Garland WA, Stoller G, Chaudhary J, Norton L, Soni RK, Philip J, Hendrickson RC, Iavarone A, Dannenberg AJ, Chodera JD, Pavletich N, Lasorella A, Campochiaro PA, Benezra R Cell Rep. 2019 Oct 1;29(1):62-75.e7. doi: 10.1016/j.celrep.2019.08.073. PMID:31577956[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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