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

100%

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

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.

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

86%

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

Acta Biochimica Polonica

2000

vol. 47

issue 4

1061-1066

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.

Structural studies of cysteine proteases and their inhibitors.

59%

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

2001

vol. 48

issue 1

1-20

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.

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3 Acta Biochimica Polonica

2 2001

1 2000

3 Ciarkowski J.

3 Drabik P.

2 Kasprzykowski F.

2 Łankiewicz L.

1 Czaplewski C.

1 Giełdoń A.

1 Grubb A.

1 Grzonka Z.

1 Jankowska E.

1 Janowski R.

1 Jaskólski M.

1 Kasprzykowska R.

1 Kaźmierkiewicz R.

1 Kozak M.

1 Politowska E.

1 Wiczk W.

1 Wieczerzak E.

1 Ślusarz R.

Search results

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.

Structural studies of cysteine proteases and their inhibitors.