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Extension of a de novo TIM barrel with a rationally designed secondary structure element
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.10.16.342774v1?rss=1
Authors: Wiese, J. G., Shanmugaratnam, S., Höcker, B.
Abstract:
The ability to construct novel enzymes is a major aim in de novo protein design. A popular enzyme fold for design attempts is the TIM barrel. This fold is a common topology for enzymes and can harbor many diverse reactions. The recently published de novo design of a four-fold symmetric TIM barrel provides a well understood minimal scaffold for potential enzyme designs. Here we explore opportunities to extend and diversify this scaffold by adding a short de novo helix on top of the barrel. Due to the size of the protein we developed a design pipeline based on computational ab initio folding that solves a less complex sub-problem focused around the helix and its vicinity and adapt it to the entire protein. We provide biochemical characterization and a high-resolution X-ray structure for one variant and compare it to our design model. The successful extension of this robust TIM-barrel scaffold opens opportunities to diversify it towards more pocket like arrangements and as such can be considered a building block for future design of binding or catalytic sites.
Copy rights belong to original authors. Visit the link for more info
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By Multimodal LLCLink to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2020.10.16.342774v1?rss=1
Authors: Wiese, J. G., Shanmugaratnam, S., Höcker, B.
Abstract:
The ability to construct novel enzymes is a major aim in de novo protein design. A popular enzyme fold for design attempts is the TIM barrel. This fold is a common topology for enzymes and can harbor many diverse reactions. The recently published de novo design of a four-fold symmetric TIM barrel provides a well understood minimal scaffold for potential enzyme designs. Here we explore opportunities to extend and diversify this scaffold by adding a short de novo helix on top of the barrel. Due to the size of the protein we developed a design pipeline based on computational ab initio folding that solves a less complex sub-problem focused around the helix and its vicinity and adapt it to the entire protein. We provide biochemical characterization and a high-resolution X-ray structure for one variant and compare it to our design model. The successful extension of this robust TIM-barrel scaffold opens opportunities to diversify it towards more pocket like arrangements and as such can be considered a building block for future design of binding or catalytic sites.
Copy rights belong to original authors. Visit the link for more info