8VTT

Meis1 homeobox domain bound to neomycin fragment

Summary for 8VTT

• Entry DOI: 10.2210/pdb8vtt/pdb
• Related: 8VTS
• Descriptor: Homeobox protein Meis1, RIBOSTAMYCIN, SULFATE ION, ... (4 entities in total)
• Functional Keywords: homeobox domain, human homeobox protein meis1, dna-binding, transcription, homeobox, nucleus, phosphoprotein, dna binding protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 8
• Total formula weight: 62837.90

Authors

Tomchick, D.R.,Ahmed, M.S.,Nguyen, N.U.N.,Sadek, H.A. (deposition date: 2024-01-27, release date: 2024-02-14, Last modification date: 2024-09-11)

Primary citation

Ahmed, M.S.,Nguyen, N.U.N.,Nakada, Y.,Hsu, C.C.,Farag, A.,Lam, N.T.,Wang, P.,Thet, S.,Menendez-Montes, I.,Elhelaly, W.M.,Lou, X.,Secco, I.,Tomczyk, M.,Zentilin, L.,Pei, J.,Cui, M.,Dos Santos, M.,Liu, X.,Liu, Y.,Zaha, D.,Walcott, G.,Tomchick, D.R.,Xing, C.,Zhang, C.C.,Grishin, N.V.,Giacca, M.,Zhang, J.,Sadek, H.A.
Identification of FDA-approved drugs that induce heart regeneration in mammals.
Nat Cardiovasc Res, 3:372-388, 2024

PubMed Abstract: Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro-Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation. Collectively, we identified FDA-approved drugs with therapeutic potential for induction of heart regeneration in mammals.

PubMed: 39183959
DOI: 10.1038/s44161-024-00450-y

Experimental method

X-RAY DIFFRACTION (2.45 Å)