Wyniki wyszukiwania

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Molecular modelling of the oxytocin receptor-bioligand interactions

100%

Politowska E., Czaplewski C., Ciarkowski J.

Acta Biochimica Polonica

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1999

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tom 46

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nr 3

Oxytocin is a nonapeptide hormone (CYIQNCPLG-NH2, OT), controlling labor and lactation in mammalian females, via interactions with specific cellular membrane receptors (OTRs). The native hormone is cyclized via a 1-6 disulfide and its receptor belongs to the GTP-binding (G) protein-coupled receptor (GPCR) family, also known as heptahelical transmembrane (7TM) or serpentine receptors. Using a technique combining multiple sequence alignments with available experimental constraints, a reliable OTR model was built. Subsequently, the OTR complexes with a selective agonist [Thr4,Gly7]OT, a selective cyclohexapeptide antagonist L-366,948 and oxytocin itself were modeled and relaxed using a constrained simulated annealing (CSA) protocol. All three ligands seem to prefer similar modes of binding to the receptor, manifested by repeating receptor residues which directly interact with the ligands. Those involved in the three complexes are putative helices: TM3: R113, K116, Q119, M123; TM4: Q171, and TM5: I201 and T205. Most of them are the equivalent residues/positions to those found in our earlier studies, regarding related vasopressin V2 receptor/bioligand interactions.

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Molecular modelling study of the role of cholesterol in the stimulation of the oxytocin receptor

88%

Politowska E., Kazmierkiewicz R., Wiegand V., Fahrenholz F., Ciarkowski J.

Acta Biochimica Polonica

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2001

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tom 48

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nr 1

Cholesterol, an integral component of membranes in Eucaryota, is a modifier of membrane properties. In vivo studies have demonstrated that cholesterol can also modulate activities of some G protein-coupled receptors (GPCRs), which are integral membrane proteins. This can result either from an effect of cholesterol on the membrane fluidity or from specific interactions of the membrane cholesterol with the receptor, as recently demonstrated for the cholecystokinin type β (CCKRβ ) or the oxytocin receptor (OTR). Using molecular modelling, we studied conformational preferences of cholesterol and several of its analogues. Subsequently, we simulated the distributions of their preferred conformations around the surface of OTR, CCKR β and a chimeric oxytocin/cholecystokinin receptor. Consequently, we suggest residues on the surface of OTR which are potentially significant in the OTR/cholesterol interaction.

3

Theoretical studies of binding modes of two covalent inhibitors of cysteine proteases

76%

Drabik P., Politowska E., Czaplewski C., Kasprzykowski F., Lankiewicz L., Ciarkowski J.

Acta Biochimica Polonica

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2000

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tom 47

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nr 4

Physiological and pathological roles of cysteine proteases make them important targets for inhibitor development. Although highly potent inhibitors of this group of enzymes are known, their major drawback is a lack of sufficient specificity. Two cysteine protease covalent inhibitors, viz. (i) Z-RL-deoxo-V-peptide-epoxysuccinyl hybrid, and (ii) Z-RLVG-methyl-, have been developed and modeled in the catalytic pocket of papain, an archetypal thiol protease. A number of configurations have been generated and relaxed for each system using the AMBER force field. The catalytic pockets S3 and S4 appear rather elusive in view of the observed inhibitors' flexibility. This suggest rather limited chances for the development of selective structure-based inhibitors of thiol proteases, designed to exploit differences in the structure of catalytic pockets of various members of this family.

Ograniczanie wyników

3 Acta Biochimica Polonica

3 Ciarkowski J.

3 Politowska E.

2 Czaplewski C.

1 Drabik P.

1 Fahrenholz F.

1 Kasprzykowski F.

1 Kazmierkiewicz R.

1 Lankiewicz L.

1 Wiegand V.

1 2001

1 2000

1 1999

Molecular modelling of the oxytocin receptor-bioligand interactions

Molecular modelling study of the role of cholesterol in the stimulation of the oxytocin receptor

Theoretical studies of binding modes of two covalent inhibitors of cysteine proteases