8vts

From Proteopedia

Meis1 homeobox domain bound to paromomycin fragment

Structural highlights

8vts is a 8 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.91Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MEIS1_MOUSE Meis1 serves as a site of viral integration in 15% of the tumors arising in BXH-2 mice that develop myeloid leukemia as a result of the expression of an ecotropic murine leukemia virus.^[1]

Function

MEIS1_MOUSE Acts as a transcriptional regulator of PAX6. Also acts as a transcriptional activator of PF4 in complex with PBX1 or PBX2. Required for hematopoiesis, megakaryocyte lineage development and vascular patterning. May function as a cofactor for HOXA7 and HOXA9 in the induction of myeloid leukemias.^[2] ^[3]

Publication Abstract from PubMed

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.

Identification of FDA-approved drugs that induce heart regeneration in mammals.,Ahmed MS, Nguyen NUN, Nakada Y, Hsu CC, Farag A, Lam NT, Wang P, Thet S, Menendez-Montes I, Elhelaly WM, Lou X, Secco I, Tomczyk M, Zentilin L, Pei J, Cui M, Dos Santos M, Liu X, Liu Y, Zaha D, Walcott G, Tomchick DR, Xing C, Zhang CC, Grishin NV, Giacca M, Zhang J, Sadek HA Nat Cardiovasc Res. 2024 Mar;3(3):372-388. doi: 10.1038/s44161-024-00450-y. Epub , 2024 Mar 11. PMID:39183959^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Moskow JJ, Bullrich F, Huebner K, Daar IO, Buchberg AM. Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice. Mol Cell Biol. 1995 Oct;15(10):5434-43. PMID:7565694 doi:10.1128/MCB.15.10.5434
↑ Zhang X, Friedman A, Heaney S, Purcell P, Maas RL. Meis homeoproteins directly regulate Pax6 during vertebrate lens morphogenesis. Genes Dev. 2002 Aug 15;16(16):2097-107. PMID:12183364 doi:10.1101/gad.1007602
↑ Azcoitia V, Aracil M, Martínez-A C, Torres M. The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Dev Biol. 2005 Apr 15;280(2):307-20. PMID:15882575 doi:10.1016/j.ydbio.2005.01.004
↑ Ahmed MS, Nguyen NUN, Nakada Y, Hsu CC, Farag A, Lam NT, Wang P, Thet S, Menendez-Montes I, Elhelaly WM, Lou X, Secco I, Tomczyk M, Zentilin L, Pei J, Cui M, Dos Santos M, Liu X, Liu Y, Zaha D, Walcott G, Tomchick DR, Xing C, Zhang CC, Grishin NV, Giacca M, Zhang J, Sadek HA. Identification of FDA-approved drugs that induce heart regeneration in mammals. Nat Cardiovasc Res. 2024 Mar;3(3):372-388. PMID:39183959 doi:10.1038/s44161-024-00450-y