6V7N
Crystal Structure of a human Lysosome Resident Glycoprotein, Lysosomal Acid Lipase, and its Implications in Cholesteryl Ester Storage Disease (CESD)
Summary for 6V7N
| Entry DOI | 10.2210/pdb6v7n/pdb |
| Descriptor | Lysosomal acid lipase/cholesteryl ester hydrolase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total) |
| Functional Keywords | lysosomal acid lipase, cholesteryl ester storage disease, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 89239.68 |
| Authors | |
| Primary citation | Rajamohan, F.,Reyes, A.R.,Tu, M.,Nedoma, N.L.,Hoth, L.R.,Schwaid, A.G.,Kurumbail, R.G.,Ward, J.,Han, S. Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease. J.Lipid Res., 61:1192-1202, 2020 Cited by PubMed Abstract: Lysosomal acid lipase (LAL) is a serine hydrolase that hydrolyzes cholesteryl ester (CE) and TGs delivered to the lysosomes into free cholesterol and fatty acids. LAL deficiency due to mutations in the LAL gene () results in accumulation of TGs and cholesterol esters in various tissues of the body leading to pathological conditions such as Wolman's disease and CE storage disease (CESD). Here, we present the first crystal structure of recombinant human LAL (HLAL) to 2.6 Å resolution in its closed form. The crystal structure was enabled by mutating three of the six potential glycosylation sites. The overall structure of HLAL closely resembles that of the evolutionarily related human gastric lipase (HGL). It consists of a core domain belonging to the classical α/β hydrolase-fold family with a classical catalytic triad (Ser-153, His-353, Asp-324), an oxyanion hole, and a "cap" domain, which regulates substrate entry to the catalytic site. Most significant structural differences between HLAL and HGL exist at the lid region. Deletion of the short helix, NLCFLLC, at the lid region implied a possible role in regulating the highly hydrophobic substrate binding site from self-oligomerization during interfacial activation. We also performed molecular dynamic simulations of dog gastric lipase (lid-open form) and HLAL to gain insights and speculated a possible role of the human mutant, H274Y, leading to CESD. PubMed: 32482718DOI: 10.1194/jlr.RA120000748 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.62 Å) |
Structure validation
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