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Sotirios Koutsopoulos, Kamal Jaffrey; Computer Modeling Analysis and Reconstruction of the Three Dimensional Structure of the Human Lysyl Oxidase-Like (LOXL-1) Protein. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2426.
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Lysyl oxidase initiates the crosslinking of collagen and elastin and plays a key role in morphogenesis and repair of the connective tissue. The enzyme family contains four lysyl oxidase-like proteins (ie, LOXL-1, LOXL-2, LOXL-3, and LOXL-4) which have a copper-binding site, residues for lysyl-tyrosyl quinine, and a cytokine receptor-like domain. Pseudoexfoliation syndrome (PEX) involves the deposition of fibrils in the eye that is the cause of an aggressive secondary glaucoma. While the exact pathomechanism of PEX-associated glaucoma is unknown, characterization of the fibrillar material suggests that the disease is due to aggregation of elastin fibers and nucleotide polymorphisms in the gene expressing LOXL-1.
The 3D structure of LOXL-1 is not known and therefore there is a significant interest in determining the conformation of a protein that may be responsible for PEX. Herein, we present preliminary molecular modeling studies to determine the 3D structure of LOXL-1. There is no protein from the lysyl-oxidase family with resolved structure and all proteins of the family have low homology with others proteins with characterized 3D structure. We used computer modeling tools and literature data to reconstruct the LOXL-1 structure and understand the functionality of the enzyme. We created a database of protein structures and identified potential structural similarities with the structure of LOXL-1. Then, we assembled parts of LOXL-1 for which we could predict their structure with confidence.
We calculated dihedral angles and added hydrogen bonds interconnecting a-helices and b-sheets. Our model is more reliable at LOXL-1’s C- and N-termini while further optimization will be required to determine the rest of the proteins structure.
Our preliminary model offers an insight into the 3D structure of LOXL-1 and provides information on the surface electrostatic properties and the relative location of a number of a-helices and b-sheets. Further work is required to optimize the interatomic interactions and reconstruct the entire enzyme structure.
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