Journal
NATURE CHEMISTRY
Volume 9, Issue 12, Pages 1157-1164Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEM.2846
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Funding
- National Science Foundation (NSF) [CHE-1413333]
- National Institutes of Health (NIH) [GM-071628, GM-048043]
- NSF [CHE-1413295, DMR-1120901]
- NIH [GM-071628, GM-054616]
- XSEDE [MCB080011]
- Direct For Mathematical & Physical Scien [1413295] Funding Source: National Science Foundation
- Division Of Chemistry [1413295] Funding Source: National Science Foundation
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1413333] Funding Source: National Science Foundation
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Protein catalysis requires the atomic-level orchestration of side chains, substrates and cofactors, and yet the ability to design a small-molecule-binding protein entirely from first principles with a precisely predetermined structure has not been demonstrated. Here we report the design of a novel protein, PS1, that binds a highly electron-deficient non-natural porphyrin at temperatures up to 100 degrees C. The high-resolution structure of holo-PS1 is in sub-angstrom agreement with the design. The structure of apo-PS1 retains the remote core packing of the holoprotein, with a flexible binding region that is predisposed to ligand binding with the desired geometry. Our results illustrate the unification of core packing and binding-site definition as a central principle of ligand-binding protein design.
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