Search results

1

Interaction of class A G protein-coupled receptors with G protein.

100%

Ślusarz R., Ciarkowski J.

Acta Biochimica Polonica

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2004

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vol. 51

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issue 1

129-136

EN

A model for interaction of class A G protein-coupled receptor with the G protein Gα subunit is proposed using the rhodopsin-transducin (RD/Gt) prototype. The model combines the resolved interactions/distances, essential in the active RD*/Gt system, with the structure of Gtα C-terminal peptide bound to RD* while stabilizing it. Assuming the interactions involve conserved parts of the partners, the model specifies the conserved Helix 2 non-polar X- - -X, Helix 3 DRY and Helix 7/8 NP- -Y- - F RD* motifs interacting with the Gtα C-terminal peptide, in compliance with the structure of the latter. A concomitant role of Gtα and Gtγ>C-termini in stabilizing RD* could possibly be resolved assuming a receptor dimer as requisite for G protein activation.

2

Theoretical models of catalytic domains of protein phosphatases 1 and 2A with Zn2+ and Mn2+ metal dications and putative bioligands in their catalytic centers.

81%

Woźniak-Celmer E., Ołdziej S., Ciarkowski J.

Acta Biochimica Polonica

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2001

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vol. 48

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issue 1

35-52

EN

The oligomeric metalloenzymes protein phosphatases dephosphorylate OH groups of Ser/Thr or Tyr residues of proteins whose actions depend on the phosphorus signal. The catalytic units of Ser/Thr protein phosphatases 1, 2A and 2B (PP1c, PP2Ac and PP2Bc, respectively), which exhibit about 45% sequence similarity, have their active centers practically identical. This feature strongly suggests that the unknown structure of PP2Ac could be successfully homology-modeled from the known structures of PP1c and/or PP2Bc. Initially, a theoretical model of PP1c was built, including a phosphate and a metal dication in its catalytic site. The latter was modeled, together with a structural hydroxyl anion, as a triangular pseudo-molecule (Zno or Mno), composed of two metal cations (double Zn2+ or Mn2+, respectively) and the OH- group. To the free PP1c two inhibitor sequences R29RRRPpTPAMLFR40 of DARPP-32 and R30RRRPpTPATLVLT42 of Inhibitor-1, and two putative substrate sequences LRRApSVA and QRRQRKpRRTI were subsequently docked. In the next step, a free PP2Ac model was built via homology re-modeling of the PP1c template and the same four sequences were docked to it. Thus, together, 20 starting model complexes were built, allowing for combination of the Zno and Mno pseudo-molecules, free enzymes and the peptide ligands docked in the catalytic sites of PP1c and PP2Ac. All models were subsequently subjected to 250-300 ps molecular dynamics using the AMBER 5.0 program. The equilibrated trajectories of the final 50 ps were taken for further analyses. The theoretical models of PP1c complexes, irrespective of the dication type, exhibited increased mobilities in the following residue ranges: 195-200, 273-278, 287-209 for the inhibitor sequences and 21-25, 194-200, 222-227, 261, 299-302 for the substrate sequences. Paradoxically, the analogous PP2Ac models appeared much more stable in similar simulations, since only their "prosegment" residues 6-10 and 14-18 exhibited an increased mobility in the inhibitor complexes while no areas of increased mobility were found in the substrate complexes. Another general observation was that the complexes with Mn dications were more stable than those with Zn dications for both PP1c and PP2Ac units.

3

Elucidation of neurophysin/bioligand interactions horn rnolecular rnodeling

80%

Kaźmierkiewicz R., Czaplewski C., Ciarkowski J.

Acta Biochimica Polonica

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1997

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vol. 44

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issue 3

453-466

4

Molecular modelling of the vasopressin V2 receptor/antagonist interactions

80%

Czaplewski C., Kaźmierkiewicz R., Ciarkowski J.

Acta Biochimica Polonica

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1998

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vol. 45

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issue 1

19-26

5

Molecular docking-based test for affinities of two ligands toward vasopressin and oxytocin receptors.

71%

Ślusarz R., Kaźmierkiewicz R., Giełdoń A., Lammek B., Ciarkowski J.

Acta Biochimica Polonica

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2001

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vol. 48

|

issue 1

131-135

EN

Molecular docking simulations are now fast developing area of research. In this work we describe an effective procedure of preparation of the receptor-ligand complexes. The amino-acid residues involved in ligand binding were identified and described.

6

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

71%

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

Acta Biochimica Polonica

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2001

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vol. 48

|

issue 1

83-93

EN

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, CCKRβ and a chimeric oxytocin/cholecystokinin receptor. Consequently, we suggest residues on the surface of OTR which are potentially significant in the OTR/cholesterol interaction.

7

Signal transmission via G protein-coupled receptors in the light of rhodopsin structure determination.

71%

Ciarkowski J., Drabik P., Giełdoń A., Kaźmierkiewicz R., Ślusarz R.

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EN

G protein-coupled receptors (GPCRs) transducing diverse external signals to cells via activation of heterotrimeric GTP-binding (G) proteins, estimated to mediate actions of 60% of drugs, had been resistant to structure determination until summer 2000. The first atomic-resolution experimental structure of a GPCR, that of dark (inactive) rhodopsin, thus provides a trustworthy 3D prototype for antagonist-bound forms of this huge family of proteins. In this work, our former theoretical GPCR models are evaluated against the new experimental template. Subsequently, a working hypothesis regarding the signal transduction mechanism by GPCRs is presented.

8

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

62%

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

Acta Biochimica Polonica

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2000

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vol. 47

|

issue 4

1061-1066

EN

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.

9

Molecular modeling of the oxytocin receptor/bioligand interactions

60%

Politowska E., Czaplewski C., Ciarkowski J.

Acta Biochimica Polonica

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1999

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vol. 46

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issue 3

581-590

10

Structural studies of cysteine proteases and their inhibitors.

42%

Grzonka Z., Jankowska E., Kasprzykowski F., Kasprzykowska R., Łankiewicz L., Wiczk W., Wieczerzak E., Ciarkowski J., Drabik P., Janowski R., Kozak M., Jaskólski M., Grubb A.

Acta Biochimica Polonica

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2001

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vol. 48

|

issue 1

1-20

EN

Cysteine proteases (CPs) are responsible for many biochemical processes occurring in living organisms and they have been implicated in the development and progression of several diseases that involve abnormal protein turnover. The activity of CPs is regulated among others by their specific inhibitors: cystatins. The main aim of this review is to discuss the structure-activity relationships of cysteine proteases and cystatins, as well as of some synthetic inhibitors of cysteine proteases structurally based on the binding fragments of cystatins.

Refine search results

Interaction of class A G protein-coupled receptors with G protein.

Theoretical models of catalytic domains of protein phosphatases 1 and 2A with Zn2+ and Mn2+ metal dications and putative bioligands in their catalytic centers.

Elucidation of neurophysin/bioligand interactions horn rnolecular rnodeling

Molecular modelling of the vasopressin V2 receptor/antagonist interactions

Molecular docking-based test for affinities of two ligands toward vasopressin and oxytocin receptors.

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

Signal transmission via G protein-coupled receptors in the light of rhodopsin structure determination.

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

Molecular modeling of the oxytocin receptor/bioligand interactions

Structural studies of cysteine proteases and their inhibitors.