engleski

MD simulations showed large conformational changes of the human free DPP III

The dipeptidyl peptidase III (DPP III) is a monozinc metalloexopeptidase that hydrolyzes dipeptides from the N-terminal of its substrates, which consist of three or more amino acids [1, 2, 3]. DPP III is thought to contribute to the final steps of normal intercellular protein catabolism, as well as to participate in the pain modulatory systems, and endogenous defense against oxidative stress [3, 4, 5, 6]. The crystal structure of the human DPP III deposited in Protein Data Bank in 2009 (3FVY) revealed two domains consisting mostly of α and  structural elements. In order to obtain clear picture of the protein flexibility long molecular dynamics (MD) simulation of the ligand free DPP III was performed [7, 8]. Our results showed that during 101 ns of the simulation the enzyme tertiary structure changed significantly. However, its secondary structure remained unchanged. The conformational change assisted by Asp372 reorientation resulted with inter domain movement in which upper and lower domains approached each other. The free energy calculations suggested that the both conformations, "open" and "close" are equally probable [8]. Further MD simulations with mutated (Asp372 to Ala372) ligand free DPP III are required to elucidate effects of the mutation on the system stability, and to verify the Asp372 role in the DPP III conformational change. [1] Ellis S, Nuenke JM (1967) J. Biol. Chem. 242, 4623-4629 [2] Abramić M, Zubanović M, Vitale Lj (1988) Biol. Chem. Hoppe-Seyler 369, 29-38 [3] Chen JM, Barrett AJ (2004) In: Barret AJ, Rawlings ND, Woessner JF (eds) Handbook of Proteolytic Enzymes, vol 1. Elsevier, Academic Press, London, pp 809-812 [4] Isac RE, Bland ND, Shirras AD. (2009) Gen. Comp. Endocr. 162, 8-17 [5] Chiba T, Li YH, Yamane T, Ogikubo O, Fukuoka M, Arai R, Takahashi S, Ohtsuka T, Ohkubo I, Matsui N (2003) Peptides 24, 773-778 [6] Liu Y, Kern JT, Walker JR, Johnson JA, Schultz PG, LUesch H (2007) Proc. Natl. Acad. Sci. USA 104, 5205-5210 [7] Tomić A, Abramić M, Špoljarić J, Agić D, Smith DM, Tomić S (2011) J. Mol. Recogn. 24, 804-814 [8] Tomić A, Tomić S, Free human DPP III molecular dynamics simulations, in preparation

free dipeptidyl peptidase III; molecular modelling; conformational change

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