Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Elucidation of conformational states, dynamics, and mechanism of binding in human κ-opioid receptor complexes
Δημιουργός/Συγγραφέας:	Leonis G. Avramopoulos A. Salmas R.E. Durdagi S. Yurtsever M. [EL] Παπαδόπουλος, Μάνθος Γ.[EN] Papadopoulos, Manthos G.
Εκδότης:	American Chemical Society
Ημερομηνία:	2014
Γλώσσα:	Αγγλικά
ISSN:	1549-9596
DOI:	10.1021/ci5002873
Άλλο:	PubMed ID: 25060329
Περίληψη:	Opioid G protein-coupled receptors (GPCRs) have been implicated in modulating pain, addiction, psychotomimesis, mood and memory, among other functions. We have employed the recently reported crystal structure of the human κ-opioid receptor (κ-OR) and performed molecular dynamics (MD), free energy, and ab initio calculations to elucidate the binding mechanism in complexes with antagonist JDTic and agonist SalA. The two systems were modeled in water and in DPPC lipid bilayers, in order to investigate the effect of the membrane upon conformational dynamics. MD and Atoms in Molecules (AIM) ab initio calculations for the complexes in water showed that each ligand was stabilized inside the binding site of the receptor through hydrogen bond interactions that involved residues Asp138 (with JDTic) and Gln115, His291, Leu212 (with SalA). The static description offered by the crystal structure was overcome to reveal a structural rearrangement of the binding pocket, which facilitated additional interactions between JDTic and Glu209/Tyr139. The role of Glu209 was emphasized, since it belongs to an extracellular loop that covers the binding site of the receptor and is crucial for ligand entrapment. The above interactions were retained in membrane complexes (SalA forms additional hydrogen bonds with Tyr139/312), except the Tyr139 interaction, which is abolished in the JDTic complex. For the first time, we report that JDTic alternates between a "V-shape" (stabilized via a water-mediated intramolecular interaction) and a more extended conformation, a feature that offers enough suppleness for effective binding. Moreover, MM-PBSA calculations showed that the more efficient JDTic binding to κ-OR compared to SalA (ΔGJDTic = -31.6 kcal mol-1, ΔGSalA = -9.8 kcal mol-1) is attributed mostly to differences in electrostatic contributions. Importantly, our results are in qualitative agreement with the experiments (ΔG JDTic,exp = -14.4 kcal mol-1, ΔGSalA,exp = -10.8 kcal mol-1). This study provides previously unattainable information on the dynamics of human κ-OR and insight on the rational design of drugs with improved pharmacological properties.
Τίτλος πηγής δημοσίευσης:	Journal of Chemical Information and Modeling
Τόμος/Κεφάλαιο:	54
Τεύχος:	8
Σελίδες:	2294-2308
Θεματική Κατηγορία:	[EL] Φαρμακευτική χημεία[EN] Pharmaceutical chemistry
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© 2014 American Chemical Society.
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο