6MGN

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

Summary for 6MGN

• Entry DOI: 10.2210/pdb6mgn/pdb
• Descriptor: Transcription factor E2-alpha, DNA-binding protein inhibitor ID-1 (3 entities in total)
• Functional Keywords: dna-binding protein inhibitor id-1, transcription factor e2-alpha isoform e47 [homo sapiens], dna binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 11726.70

Authors

Benezra, R.,Pavletich, N.P.,Gall, A.-L.,Goldgur, Y. (deposition date: 2018-09-14, release date: 2019-09-18, Last modification date: 2023-10-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.901 Å)