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De novo design of a homo-trimeric amantadine-binding protein

Journal Article · · eLife
DOI:https://doi.org/10.7554/eLife.47839· OSTI ID:1598025
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [3];  [8];  [2];  [9]
  1. Univ. of Washington, Seattle, WA (United States); Sana Biotechnology, Inc., Seattle, WA (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  3. Univ. of California, Santa Cruz, CA (United States)
  4. Univ. of Washington, Seattle, WA (United States); Lyell Immunopharma, Inc., Seattle, WA (United States)
  5. Univ. of Washington, Seattle, WA (United States); Univ. of California, Berkeley, CA (United States)
  6. Graz University of Technology (Austria)
  7. Univ. of California, San Francisco, CA (United States)
  8. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); St. Jude Children’s Research Hospital, Memphis, TN (United States)
  9. Univ. of Washington, Seattle, WA (United States)
+ Show Author Affiliations
The computational design of a symmetric protein homo-oligomer that binds a symmetry-matched small molecule larger than a metal ion has not yet been achieved. We used de novo protein design to create a homo-trimeric protein that binds the C3 symmetric small molecule drug amantadine with each protein monomer making identical interactions with each face of the small molecule. Solution NMR data show that the protein has regular three-fold symmetry and undergoes localized structural changes upon ligand binding. A high-resolution X-ray structure reveals a close overall match to the design model with the exception of water molecules in the amantadine binding site not included in the Rosetta design calculations, and a neutron structure provides experimental validation of the computationally designed hydrogen-bond networks. Exploration of approaches to generate a small molecule inducible homo-trimerization system based on the design highlight challenges that must be overcome to computationally design such systems.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); Washington Research Foundation; National Inst. of General Medical Sciences; Burroughs Wellcome Fund; Howard Hughes Medical Inst.; NIH
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1598025
Journal Information:
eLife, Journal Name: eLife Journal Issue: 2019 Vol. 8; ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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