6MGN

mouse Id1 (51-104) - human hE47 (348-399) complex

6MGN の概要

• エントリーDOI: 10.2210/pdb6mgn/pdb
• 分子名称: Transcription factor E2-alpha, DNA-binding protein inhibitor ID-1 (3 entities in total)
• 機能のキーワード: dna-binding protein inhibitor id-1, transcription factor e2-alpha isoform e47 [homo sapiens], dna binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 11726.70

構造登録者

Benezra, R.,Pavletich, N.P.,Gall, A.-L.,Goldgur, Y. (登録日: 2018-09-14, 公開日: 2019-09-18, 最終更新日: 2023-10-11)

主引用文献

Wojnarowicz, P.M.,Lima E Silva, R.,Ohnaka, M.,Lee, S.B.,Chin, Y.,Kulukian, A.,Chang, S.H.,Desai, B.,Garcia Escolano, M.,Shah, R.,Garcia-Cao, M.,Xu, S.,Kadam, R.,Goldgur, Y.,Miller, M.A.,Ouerfelli, O.,Yang, G.,Arakawa, T.,Albanese, S.K.,Garland, W.A.,Stoller, G.,Chaudhary, J.,Norton, L.,Soni, R.K.,Philip, J.,Hendrickson, R.C.,Iavarone, A.,Dannenberg, A.J.,Chodera, J.D.,Pavletich, N.,Lasorella, A.,Campochiaro, P.A.,Benezra, R.
A Small-Molecule Pan-Id Antagonist Inhibits Pathologic Ocular Neovascularization.
Cell Rep, 29:62-75.e7, 2019

PubMed Abstract: Id 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.

PubMed: 31577956
DOI: 10.1016/j.celrep.2019.08.073

実験手法

X-RAY DIFFRACTION (1.901 Å)