7umo

From Proteopedia

Structure of Unc119-inhibitor complex.

Structural highlights

7umo is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

U119A_HUMAN Idiopathic CD4 lymphocytopenia;Cone rod dystrophy. Defects in UNC119 may be a cause of cone-rod dystrophy. A mutation was found in a 57-year-old woman with late-onset cone-rod dystrophy: from 40 year old, the patient suffered from poor night vision, defective color vision and light-sensitivity. At 57 year old, she displayed reduced visual acuity, myopa, macular atrophy and pericentral ring scotomas. The disease was caused by a heterozygous mutation causing premature termination and truncated UNC119 protein with dominant-negative effect.

Function

U119A_HUMAN Myristoyl-binding protein that acts as a cargo adapter: specifically binds the myristoyl moiety of a subset of N-terminally myristoylated proteins and is required for their localization. Binds myristoylated GNAT1 and is required for G-protein localization and trafficking in sensory neurons. Binds myristoylated NPHP3; however, in contrast to UNC119B, does not seem to play a major role in ciliary membrane localization of NPHP3. Does not bind all myristoylated proteins. Probably plays a role in trafficking proteins in photoreceptor cells.^[1] ^[2]

Publication Abstract from PubMed

Insulin resistance (IR) is the root cause of type II diabetes, yet no safe treatment is available to address it. Using a high throughput compatible assay that measures real-time translocation of the glucose transporter glucose transporter 4 (GLUT4), we identified small molecules that potentiate insulin action. In vivo, these insulin sensitizers improve insulin-stimulated GLUT4 translocation, glucose tolerance, and glucose uptake in a model of IR. Using proteomic and CRISPR-based approaches, we identified the targets of those compounds as Unc119 proteins and solved the structure of Unc119 bound to the insulin sensitizer. This study identifies compounds that have the potential to be developed into diabetes treatment and establishes Unc119 proteins as targets for improving insulin sensitivity.

Insulin sensitization by small molecules enhancing GLUT4 translocation.,Yin TC, Van Vranken JG, Srivastava D, Mittal A, Buscaglia P, Moore AE, Verdinez JA, Graham AE, Walsh SA, Acevedo MA, Kerns RJ, Artemyev NO, Gygi SP, Sebag JA Cell Chem Biol. 2023 Jun 28:S2451-9456(23)00190-3. doi: , 10.1016/j.chembiol.2023.06.012. PMID:37453421^[3]

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

References

↑ Wright KJ, Baye LM, Olivier-Mason A, Mukhopadhyay S, Sang L, Kwong M, Wang W, Pretorius PR, Sheffield VC, Sengupta P, Slusarski DC, Jackson PK. An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 to the primary cilium. Genes Dev. 2011 Nov 15;25(22):2347-60. doi: 10.1101/gad.173054.111. PMID:22085962 doi:10.1101/gad.173443.111
↑ Zhang H, Constantine R, Vorobiev S, Chen Y, Seetharaman J, Huang YJ, Xiao R, Montelione GT, Gerstner CD, Davis MW, Inana G, Whitby FG, Jorgensen EM, Hill CP, Tong L, Baehr W. UNC119 is required for G protein trafficking in sensory neurons. Nat Neurosci. 2011 Jun 5. PMID:21642972 doi:10.1038/nn.2835
↑ Yin TC, Van Vranken JG, Srivastava D, Mittal A, Buscaglia P, Moore AE, Verdinez JA, Graham AE, Walsh SA, Acevedo MA, Kerns RJ, Artemyev NO, Gygi SP, Sebag JA. Insulin sensitization by small molecules enhancing GLUT4 translocation. Cell Chem Biol. 2023 Jun 28:S2451-9456(23)00190-3. PMID:37453421 doi:10.1016/j.chembiol.2023.06.012