Shahoei_2022_Front.Mol.Biosci_9_935375

Reference

Title : Molecular Modeling of ABHD5 Structure and Ligand Recognition - Shahoei_2022_Front.Mol.Biosci_9_935375
Author(s) : Shahoei R , Pangeni S , Sanders MA , Zhang H , Mladenovic-Lucas L , Roush WR , Halvorsen G , Kelly CV , Granneman JG , Huang YM
Ref : Front Mol Biosci , 9 :935375 , 2022
Abstract :

Alpha/beta hydrolase domain-containing 5 (ABHD5), also termed CGI-58, is the key upstream activator of adipose triglyceride lipase (ATGL), which plays an essential role in lipid metabolism and energy storage. Mutations in ABHD5 disrupt lipolysis and are known to cause the Chanarin-Dorfman syndrome. Despite its importance, the structure of ABHD5 remains unknown. In this work, we combine computational and experimental methods to build a 3D structure of ABHD5. Multiple comparative and machine learning-based homology modeling methods are used to obtain possible models of ABHD5. The results from Gaussian accelerated molecular dynamics and experimental data of the apo models and their mutants are used to select the most likely model. Moreover, ensemble docking is performed on representative conformations of ABHD5 to reveal the binding mechanism of ABHD5 and a series of synthetic ligands. Our study suggests that the ABHD5 models created by deep learning-based methods are the best candidate structures for the ABHD5 protein. The mutations of E41, R116, and G328 disturb the hydrogen bonding network with nearby residues and suppress membrane targeting or ATGL activation. The simulations also reveal that the hydrophobic interactions are responsible for binding sulfonyl piperazine ligands to ABHD5. Our work provides fundamental insight into the structure of ABHD5 and its ligand-binding mode, which can be further applied to develop ABHD5 as a therapeutic target for metabolic disease and cancer.

PubMedSearch : Shahoei_2022_Front.Mol.Biosci_9_935375
PubMedID: 35836935
Gene_locus related to this paper: human-ABHD5 , mouse-abhd5

Related information

Inhibitor SR-3133    SR-3134    SR-4559
Gene_locus SR-3133    SR-3134    SR-4559    human-ABHD5    mouse-abhd5

Citations formats

Shahoei R, Pangeni S, Sanders MA, Zhang H, Mladenovic-Lucas L, Roush WR, Halvorsen G, Kelly CV, Granneman JG, Huang YM (2022)
Molecular Modeling of ABHD5 Structure and Ligand Recognition
Front Mol Biosci 9 :935375

Shahoei R, Pangeni S, Sanders MA, Zhang H, Mladenovic-Lucas L, Roush WR, Halvorsen G, Kelly CV, Granneman JG, Huang YM (2022)
Front Mol Biosci 9 :935375