Computational investigation of conformational variability and allostery in cathepsin K and other related peptidases.
Allosteric targeting is progressively gaining ground as a strategy in drug design. Its success, however, depends on our knowledge of the investigated system. In the case of the papain-like cysteine peptidase cathepsin K, a major obstacle in our understanding of allostery is represented by the lack o...
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0182387&type=printable |
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| author | Marko Novinec |
| author_facet | Marko Novinec |
| author_sort | Marko Novinec |
| collection | DOAJ |
| description | Allosteric targeting is progressively gaining ground as a strategy in drug design. Its success, however, depends on our knowledge of the investigated system. In the case of the papain-like cysteine peptidase cathepsin K, a major obstacle in our understanding of allostery is represented by the lack of observable conformational change at the active site. This makes it difficult to understand how binding of effectors at known allosteric sites translates into modified enzyme activity. Herein, we address this issue by a computational approach based on experimental data. We analyze the conformational space of the papain-like family and the positioning of cathepsin K within it using principal component analysis and molecular dynamics simulations. We show that human cathepsin L-like endopeptidases (cathepsins L, K, S and V) adopt similar conformations which are distinct from their non-animal counterparts and other related peptidases. Molecular dynamics simulations show that the conformation of cathepsin K is influenced by known allosteric effectors, chondroitin sulfate and the small molecules NSC13345 and NSC94914. Importantly, all effectors affect the geometry of the active site around sites S1 and S2 that represent the narrowest part of the active site cleft and the major specificity determinant in papain-like endopeptidases. The effectors act by stabilizing pre-existing conformational states according to a two-state model and thereby facilitate or hinder the binding of substrate into the active site, as shown by molecular docking simulations. Comparison with other related enzymes shows that similar conformational variability and, by implication, allostery also exist in other papain-like endopeptidases. |
| format | Article |
| id | doaj-art-ef1dc742a3c044768bcdc812fbc9ade0 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-ef1dc742a3c044768bcdc812fbc9ade02025-08-20T02:45:30ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01128e018238710.1371/journal.pone.0182387Computational investigation of conformational variability and allostery in cathepsin K and other related peptidases.Marko NovinecAllosteric targeting is progressively gaining ground as a strategy in drug design. Its success, however, depends on our knowledge of the investigated system. In the case of the papain-like cysteine peptidase cathepsin K, a major obstacle in our understanding of allostery is represented by the lack of observable conformational change at the active site. This makes it difficult to understand how binding of effectors at known allosteric sites translates into modified enzyme activity. Herein, we address this issue by a computational approach based on experimental data. We analyze the conformational space of the papain-like family and the positioning of cathepsin K within it using principal component analysis and molecular dynamics simulations. We show that human cathepsin L-like endopeptidases (cathepsins L, K, S and V) adopt similar conformations which are distinct from their non-animal counterparts and other related peptidases. Molecular dynamics simulations show that the conformation of cathepsin K is influenced by known allosteric effectors, chondroitin sulfate and the small molecules NSC13345 and NSC94914. Importantly, all effectors affect the geometry of the active site around sites S1 and S2 that represent the narrowest part of the active site cleft and the major specificity determinant in papain-like endopeptidases. The effectors act by stabilizing pre-existing conformational states according to a two-state model and thereby facilitate or hinder the binding of substrate into the active site, as shown by molecular docking simulations. Comparison with other related enzymes shows that similar conformational variability and, by implication, allostery also exist in other papain-like endopeptidases.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0182387&type=printable |
| spellingShingle | Marko Novinec Computational investigation of conformational variability and allostery in cathepsin K and other related peptidases. PLoS ONE |
| title | Computational investigation of conformational variability and allostery in cathepsin K and other related peptidases. |
| title_full | Computational investigation of conformational variability and allostery in cathepsin K and other related peptidases. |
| title_fullStr | Computational investigation of conformational variability and allostery in cathepsin K and other related peptidases. |
| title_full_unstemmed | Computational investigation of conformational variability and allostery in cathepsin K and other related peptidases. |
| title_short | Computational investigation of conformational variability and allostery in cathepsin K and other related peptidases. |
| title_sort | computational investigation of conformational variability and allostery in cathepsin k and other related peptidases |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0182387&type=printable |
| work_keys_str_mv | AT markonovinec computationalinvestigationofconformationalvariabilityandallosteryincathepsinkandotherrelatedpeptidases |