Molecular Playground/DnaK: Difference between revisions
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===Function=== | ===Function=== | ||
DnaK binds stretches (7-8 residues in length) of exposed hydrophobic residues of its client proteins in order to prevent their aggregation.[http://www.ncbi.nlm.nih.gov/pubmed/14740253] Upon ATP binding, the NBD subdomains rotate relative to each other and induce a conformational change in the NBD (compare the <scene name='60/609794/Subdomain_iib/1'>ADP-bound</scene> NBD to the <scene name='60/609794/Nbd-atp/ | DnaK binds stretches (7-8 residues in length) of exposed hydrophobic residues of its client proteins in order to prevent their aggregation.[http://www.ncbi.nlm.nih.gov/pubmed/14740253] Upon ATP binding, the NBD subdomains rotate relative to each other and induce a conformational change in the NBD (compare the <scene name='60/609794/Subdomain_iib/1'>ADP-bound</scene> NBD to the <scene name='60/609794/Nbd-atp/2'>ATP-bound</scene> form.[http://www.ncbi.nlm.nih.gov/pubmed/21482798] When ATP binds the NBD, the interdomain linker communicates the allosteric signal to the SBD that induces a conformational change in the SBD, causing the alpha-helical lid to dock onto the NBD. Compare the <scene name='60/609794/Sbd_open/2'>open</scene> form of the SBD (when the NBD binds ATP) and the <scene name='60/609794/Helical_lid/1'>closed</scene> form of the SBD (when the NBD binds ADP).[http://www.ncbi.nlm.nih.gov/pubmed/17434124?dopt=Abstract] The SBD has low substrate affinity in the 'open' conformation, but high substrate affinity in the 'closed' conformation.[http://www.ncbi.nlm.nih.gov/pubmed/24012426] Alternating cycles of binding and release allow DnaK to unfold kinetically trapped intermediates and allow the client protein to refold to its native state.[http://www.ncbi.nlm.nih.gov/pubmed/20953191] Recently, a third 'allosterically active' state of DnaK has been discovered. In this state, the two domains remain undocked, with the SBD retaining high substrate affinity, but the interdomain linker is bound to the NBD. This state occurs when both ATP and substrate are bound simultaneously and has not yet been crystallized.[http://www.ncbi.nlm.nih.gov/pubmed/23217711] | ||
===Drug Target=== | ===Drug Target=== | ||
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5. Wegele H. et al. Rev Physiol Biochem Pharmacol 2004 | 5. Wegele H. et al. Rev Physiol Biochem Pharmacol 2004 | ||
6. | 6. Zhuravleva A. et al. Proc Natl Acad Sci USA 2011 | ||
7. | 7. Swain JF. et al. Mol Cell 2007 | ||
8. | 8. Mayer MP. Trends Biochem Sci 2013 | ||
9. | 9. Sharma SK. et al. Nat Chem Bio 2010 | ||
10. | 10. Zhuravleva A. et al. Cell 2012 | ||
11. | 11. Li X. et al. ACS Med Chem Lett 2013 | ||
12. Assimon VA. et al. Curr Pharm Des 2013 | |||
15. Powers ET. et al. Cell Rep 2012 | |||