2000
DOI: 10.1016/s0969-2126(00)00121-0
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The structure of a serpin–protease complex revealed by intramolecular distance measurements using donor–donor energy migration and mapping of interaction sites

Abstract: The data clearly demonstrate that serpin inhibition involves reactive-centre cleavage followed by full-loop insertion whereby the covalently linked protease is translocated from one pole of the inhibitor to the opposite one.

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Cited by 72 publications
(66 citation statements)
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“…If one assumes on the one hand that there is an equilibrium between two forms of the final complex, one in which some catalytic activity of the proteinase is left and one in which the catalytic activity is fully abolished and on the other hand that the proportion of these two forms varies with each serpin-proteinase pair, we may easily explain the data of Plotnick et al (38). Our data may also provide an explanation to the apparently contradictory results obtained by another team in two consecutive papers relating cross-linking experiments on the same serpin-proteinase pair (40,41). In the first paper using one type of cross-linking agent, the authors came to the conclusion that the enzyme was trapped in an intermediate position, whereas, in the second paper with a different cross-linking agent, the proteinase seemed to be in a position compatible with a full loop insertion.…”
Section: Discussionsupporting
confidence: 52%
“…If one assumes on the one hand that there is an equilibrium between two forms of the final complex, one in which some catalytic activity of the proteinase is left and one in which the catalytic activity is fully abolished and on the other hand that the proportion of these two forms varies with each serpin-proteinase pair, we may easily explain the data of Plotnick et al (38). Our data may also provide an explanation to the apparently contradictory results obtained by another team in two consecutive papers relating cross-linking experiments on the same serpin-proteinase pair (40,41). In the first paper using one type of cross-linking agent, the authors came to the conclusion that the enzyme was trapped in an intermediate position, whereas, in the second paper with a different cross-linking agent, the proteinase seemed to be in a position compatible with a full loop insertion.…”
Section: Discussionsupporting
confidence: 52%
“…However, even making the extremely unlikely assumption that 2 in the E*I* complex has its upper limit value of 4.0 (corresponding to the two fluorophores being held rigidly parallel to one another with aligned dipoles) leads to an upper limit fluorophore distance of only 42.6 Å, well below the value demanded by the fully inserted model. Although our results appear incompatible with the crystal structure of the trypsin*antitrypsin* complex, both sets of results, as well as the apparently contradictory results of others (15,16), can be rationalized within the general mechanism for serpin⅐proteinase complex formation that we propose in Fig. 6, which is based in part on the recent results of Gooptu et al (19) (see below).…”
Section: Discussioncontrasting
confidence: 91%
“…Finally, feature c also rationalizes the apparent conflict in the results of Fa et al (16), discussed above, and those of Bijnens et al (17), working with an essentially identical serpinproteinase pair. The latter workers report that monoclonal antibodies binding to an epitope comprising residues 128 -131 in helix F and K 154 in the turn connecting helix F to s3A, at the bottom of the serpin, bind equally well to active PAI-1 and to the PAI-1⅐t-PA complex.…”
Section: Discussionsupporting
confidence: 69%
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“…Although there are fluorescence (8,(11)(12)(13) and NMR (14,15) data for several covalent serpin-proteinase complexes that all indicate that proteinase translocation is a common aspect of the mechanism, there is only a single x-ray structure of such a complex that provides the details of the molecular structure and rearrangement, that is, of the ␣ 1 PI-trypsin complex (10). The structure confirms the expectations of active site distortion and steric compression between serpin and proteinase and provides the quantitation of the movements of the catalytic residues and the serpin substrate noted above.…”
mentioning
confidence: 99%