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Computational desig...
Computational design of enone-binding proteins with catalytic activity for the Morita-Baylis-Hillman reaction
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- Bjelic, Sinisa (author)
- University of Washington, USA
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- Nivón, Lucas G (author)
- University of Washington, USA
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- Çelebi-Ölçüm, Nihan (author)
- University of California, USA ; Yeditepe University, Turkey
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- Kiss, Gert (author)
- University of California, USA
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Rosewall, Carolyn F (author)
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Lovick, Helena M (author)
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Ingalls, Erica L (author)
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- Gallaher, Jasmine Lynn (author)
- University of Washington, USA
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- Seetharaman, Jayaraman (author)
- Columbia University, USA
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- Lew, Scott (author)
- Columbia University, USA
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- Montelione, Gaetano Thomas (author)
- Columbia University, USA
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- Hunt, John Francis (author)
- Columbia University, USA
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Michael, Forrest Edwin (author)
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- Houk, K N (author)
- University of California, USA
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- Baker, David (author)
- University of Washington, USA
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(creator_code:org_t)
- 2013-01-30
- 2013
- English.
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In: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 8:4, s. 749-757
- Related links:
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- The Morita-Baylis-Hillman reaction forms a carbon-carbon bond between the α-carbon of a conjugated carbonyl compound and a carbon electrophile. The reaction mechanism involves Michael addition of a nucleophile catalyst at the carbonyl β-carbon, followed by bond formation with the electrophile and catalyst disassociation to release the product. We used Rosetta to design 48 proteins containing active sites predicted to carry out this mechanism, of which two show catalytic activity by mass spectrometry (MS). Substrate labeling measured by MS and site-directed mutagenesis experiments show that the designed active-site residues are responsible for activity, although rate acceleration over background is modest. To characterize the designed proteins, we developed a fluorescence-based screen for intermediate formation in cell lysates, carried out microsecond molecular dynamics simulations, and solved X-ray crystal structures. These data indicate a partially formed active site and suggest several clear avenues for designing more active catalysts.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- Biokemi
- Biochemistry
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Bjelic, Sinisa
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Nivón, Lucas G
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Çelebi-Ölçüm, Ni ...
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Kiss, Gert
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Rosewall, Caroly ...
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Lovick, Helena M
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show more...
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Ingalls, Erica L
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Gallaher, Jasmin ...
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Seetharaman, Jay ...
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Lew, Scott
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Montelione, Gaet ...
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Hunt, John Franc ...
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Michael, Forrest ...
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Houk, K N
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Baker, David
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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ACS Chemical Bio ...
- By the university
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Linnaeus University