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Computational explo...
Computational exploration of the binding mode of heme-dependent stimulators into the active catalytic domain of soluble guanylate cyclase
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- Agullo, Luis (författare)
- Univ Vic Cent Univ Catalonia UVIC UCC, Dept Syst Biol, U Sci Tech, Sagrada Familia 7, Vic 08500, Spain.
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- Buch, Ignasi (författare)
- Hosp Del Mar Med Res Inst IMIM, Computat Biophys Lab, Barcelona 08003, Spain.
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- Gutierrez-de-Teran, Hugo (författare)
- Uppsala universitet,Beräkningsbiologi och bioinformatik
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- Garcia-Dorado, David (författare)
- Vall DHebron Res Inst VHIR, Cardiocirculatory Pathol Grp, Barcelona 08035, Spain.
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- Villa-Freixa, Jordi (författare)
- Univ Vic Cent Univ Catalonia UVIC UCC, Dept Syst Biol, U Sci Tech, Sagrada Familia 7, Vic 08500, Spain.
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Univ Vic Cent Univ Catalonia UVIC UCC, Dept Syst Biol, U Sci Tech, Sagrada Familia 7, Vic 08500, Spain Hosp Del Mar Med Res Inst IMIM, Computat Biophys Lab, Barcelona 08003, Spain. (creator_code:org_t)
- 2016-07-13
- 2016
- Engelska.
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Ingår i: Proteins. - : Wiley. - 0887-3585 .- 1097-0134. ; 84:10, s. 1534-1548
- Relaterad länk:
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http://dspace.uvic.c...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Soluble guanylate cyclase (sGC), the main target of nitric oxide (NO), has been proven to have a significant role in coronary artery disease, pulmonary hypertension, erectile dysfunction, and myocardial infarction. One of its agonists, BAY 41-2272 (Riociguat), has been recently approved for treatment of pulmonary arterial hypertension (PHA), while some others are in clinical phases of development. However, the location of the binding sites for the two known types of agonists, heme-dependent stimulators and heme-independent activators, is a matter of debate, particularly for the first group where both a location on the regulatory (H-NOX) and on the catalytic domain have been suggested by different authors. Here, we address its potential location on the catalytic domain, the unique well characterized at the structural level, by an in silico approach. Homology models of the catalytic domain of sGC in inactive or active conformations were constructed using the structure of previously described crystals of the catalytic domains of inactive sGCs (2WZ1, 3ET6) and of active adenylate cyclase (1CJU). Each model was submitted to six independent molecular dynamics simulations of about 1 s. Docking of YC-1, a classic heme-dependent stimulator, to all frames of representative trajectories of inactive and active conformations, followed by calculation of absolute binding free energies with the linear interaction energy (LIE) method, revealed a potential high-affinity binding site on the active structure. The site, located between the pseudo-symmetric and the catalytic site just over the loop (2)-(3), does not overlap with the forskolin binding site on adenylate cyclases.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Nyckelord
- homology modeling
- molecular dynamics simulations
- YC-1 docking
- linear interaction energy
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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