A 3D–Predicted Structure of the Amine Oxidase Domain of Lysyl Oxidase–Like 2

Lysyl oxidase–like 2 (LOXL2) has been recognized as an attractive drug target for anti–fibrotic and anti–tumor therapies. However, the structure–based drug design of LOXL2 has been very challenging due to the lack of structural information of the catalytically–competent LOXL2. In this study; we generated a 3D–predicted structure of the C–terminal amine oxidase domain of LOXL2 containing the lysine tyrosylquinone (LTQ) cofactor from the 2.4Å crystal structure of the Zn(2+)–bound precursor (lacking LTQ; PDB:5ZE3); this was achieved by molecular modeling and molecular dynamics simulation based on our solution studies of a mature LOXL2 that is inhibited by 2–hydrazinopyridine. The overall structures of the 3D–modeled mature LOXL2 and the Zn(2+)–bound precursor are very similar (RMSD = 1.070Å), and disulfide bonds are conserved. The major difference of the mature and the precursor LOXL2 is the secondary structure of the pentapeptide (His652–Lys653–Ala654–Ser655–Phe656) containing Lys653 (the precursor residue of the LTQ cofactor). We anticipate that this peptide is flexible in solution to accommodate the conformation that enables the LTQ cofactor formation as opposed to the β–sheet observed in 5ZE3. We discuss the active site environment surrounding LTQ and Cu(2+) of the 3D–predicted structure.