Druggable Protein Interaction Sites Are More Predisposed to Surface Pocket Formation than the Rest of the Protein Surface
dc.contributor.author | Johnson, David K. | |
dc.contributor.author | Karanicolas, John | |
dc.date.accessioned | 2014-03-19T15:28:11Z | |
dc.date.available | 2014-03-19T15:28:11Z | |
dc.date.issued | 2013-03-07 | |
dc.identifier.citation | Johnson, D. K., & Karanicolas, J. (2013). Druggable Protein Interaction Sites Are More Predisposed to Surface Pocket Formation than the Rest of the Protein Surface. PLoS Comput Biol, 9(3). http://dx.doi.org/10.1371/journal.pcbi.1002951 | |
dc.identifier.uri | http://hdl.handle.net/1808/13252 | |
dc.description.abstract | Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests that many protein interaction surfaces may not be intrinsically “druggable” by small molecules, and elevates in importance the few successful examples as model systems for improving our fundamental understanding of druggability. Here we describe an approach for exploring protein fluctuations enriched in conformations containing surface pockets suitable for small molecule binding. Starting from a set of seven unbound protein structures, we find that the presence of low-energy pocket-containing conformations is indeed a signature of druggable protein interaction sites and that analogous surface pockets are not formed elsewhere on the protein. We further find that ensembles of conformations generated with this biased approach structurally resemble known inhibitor-bound structures more closely than equivalent ensembles of unbiased conformations. Collectively these results suggest that “druggability” is a property encoded on a protein surface through its propensity to form pockets, and inspire a model in which the crude features of the predisposed pocket(s) restrict the range of complementary ligands; additional smaller conformational changes then respond to details of a particular ligand. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention. | |
dc.description.sponsorship | This work was supported by grants from the National Center for Research Resources (5P30RR030926) and the National Institute of General Medical Sciences (1R01GM099959 and 8P30GM103495) of the National Institutes of Health, and the Alfred P. Sloan Fellowship (JK). | |
dc.publisher | Public Library of Science | |
dc.rights | ©2013 Johnson, Karanicolas. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Biochemical simulation | |
dc.subject | Complement inhibitors | |
dc.subject | Crystal structure | |
dc.subject | Human papollomavirus infection | |
dc.subject | Protein interactions | |
dc.subject | Protein structure | |
dc.subject | Small molecules | |
dc.subject | Structural proteins | |
dc.title | Druggable Protein Interaction Sites Are More Predisposed to Surface Pocket Formation than the Rest of the Protein Surface | |
dc.type | Article | |
kusw.kuauthor | Johnson, David K. | |
kusw.kuauthor | Karanicolas, John | |
kusw.kudepartment | Molecular Biosciences | |
kusw.oastatus | fullparticipation | |
dc.identifier.doi | 10.1371/journal.pcbi.1002951 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item meets KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: ©2013 Johnson, Karanicolas. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.