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Pregled bibliografske jedinice broj: 718539

Časopis

Autori: Tomić, Antonija; Tomić, Sanja
Naslov: Hunting the human DPP III active conformation : combined thermodynamic and QM/MM calculations
( Hunting the human DPP III active conformation : combined thermodynamic and QM/MM calculations )
Izvornik: Dalton transactions (1477-9226) 43 (2014); 15503-15514
Vrsta rada: članak
Ključne riječi: human dipeptidyl-peptidase III; zinc coordination; substrate specificity; amino acid propensity
( human dipeptidyl-peptidase III; zinc coordination; substrate specificity; amino acid propensity )
Sažetak:
Multiple choices of the protein active conformations in flexible metalloenzymes complicate study of their catalytic mechanism. We used three different conformations of human dipeptidyl-peptidase III (DPP III) to investigate the influence of the protein environment on ligand binding and the Zn2+ coordination. MD simulations followed by calculations of binding free energy components accomplished for a series of DPP III substrates, both synthetic and natural, revealed that binding of the β-strand shaped substrate to the five-stranded β-core of the compact DPP III form (in antiparallel fashion) is the preferred binding mode, in agreement with the experimentally determined structure of the DPP III inactive mutant-tynorphin complex (Bezerra et al., Proc. Natl. Acad. Sci. U. S. A., 2012, 109, 6525). Previously it was proposed that the catalytic mechanism of DPP III is similar to that of thermolysin, which assumes exchange of five and four coordinated Zn2+, and activation of Zn-bound water by a nearby Glu. Our QM/MM calculations, performed for a total of 18 protein structures with different zinc ion environments, revealed that the 5-coordinated metal ion is more favourable than the 6-coordinated one in only the most compact DPP III form. Besides, in this structure E451 is H-bonded to the metal ion coordinating water. Also, our study revealed two constraints for the broad substrate specificity of DPP III. One is the possibility of the substrate adopting the β-strand shape and the other is its charged N-terminus. Altogether, we assume that the human DPP III active conformation would be the most compact form, similar to the “closed X-ray” DPP III structure.
Projekt / tema: 022-0222148-2822, 098-1191344-2860
Izvorni jezik: eng
Rad je indeksiran u
bazama podataka:
Current Contents Connect (CCC)
MEDLINE
Scopus
SCI-EXP, SSCI i/ili A&HCI
Science Citation Index Expanded (SCI-EXP) (sastavni dio Web of Science Core Collectiona)
Kategorija: Znanstveni
Znanstvena područja:
Kemija
URL Internet adrese: http://pubs.rsc.org/en/content/articlelanding/2014/dt/c4dt02003k#!divAbstract
Broj citata:
Altmetric:
DOI: 10.1039/C4DT02003K
URL cjelovitog teksta:
Google Scholar: Hunting the human DPP III active conformation : combined thermodynamic and QM/MM calculations
Upisao u CROSBI: Antonija Tomić (Antonija.Tomic@irb.hr), 3. Lis. 2014. u 11:00 sati



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