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Molecular dynamics simulations of ligands binding into the active site of human dipeptidyl-peptidases (DPPIII)


Tomić, Antonija; Abramić, Marija; Smith, David; Tomić, Sanja
Molecular dynamics simulations of ligands binding into the active site of human dipeptidyl-peptidases (DPPIII) // Book of Abstracts of the EMBO Young Scientists Forum
Zagreb, Hrvatska, 2009. str. 53-53 (poster, nije recenziran, sažetak, znanstveni)


Naslov
Molecular dynamics simulations of ligands binding into the active site of human dipeptidyl-peptidases (DPPIII)

Autori
Tomić, Antonija ; Abramić, Marija ; Smith, David ; Tomić, Sanja

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Book of Abstracts of the EMBO Young Scientists Forum / - , 2009, 53-53

Skup
EMBO Young Scientists Forum

Mjesto i datum
Zagreb, Hrvatska, 15.-17.06.2009

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
Dipeptidyl-peptidases; molecular dynamics simulations; ligands binding

Sažetak
Dipeptidyl-peptidases III (peptidase family M49) are zinc-dependent enzymes that specifically cleave the first two amino acids from the N terminus of different length peptides. This zinc-dependent enzyme has been recently recognized among metallopeptidases, based on the unique structural motif, hexapeptide HELLGH, which harbours the predicted active site residues. Besides its contribution in normal protein catabolism, the regulatory and pathophysiological role for DPPIII was suggested, however molecular mechanism of its action is still unknown. Recently determined crystal structure of human DPPIII (PDB code 3FVY) enabled detailed molecular modelling study. In order to understand mechanism of substrates (Arg-Arg-2naphthylamide and Ala-Ala-2naphthylamide) and inhibitor (Tyr-Phe-hydroxamate) binding into the active site of H-DPPIII we performed molecular modelling study using the Amber10 program suite. The initial structures were built in program Insight II (http://accelrys.com/products/insight/) and the steered molecular dynamics simulations were performed to determine possible orientations of the ligands in binding site. We have determined similar binding of the ligands (inhibitor and substrates) into the DPPIII active site. Namely the hydrogen bonds formed during molecular dynamics simulations are mostly conserved in all tree complexes. The zinc-binding site is built up by His-450, Glu-451 and His-455 belonging to the first conserved (450HELLGH455) signature motif, Glu-508 which is part of the second conserved motif (507EECRAE512), water molecule and carbonyl group belonging to the ligand second peptide bond from N terminus . Longer simulations aimed to study stability of these complexes and to determine effects of amino acids mutations on ligands binding have been started.

Izvorni jezik
Engleski

Znanstvena područja
Kemija



POVEZANOST RADA


Projekt / tema
06M1801

Ustanove
Institut "Ruđer Bošković", Zagreb