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Stereoelectronic and steric effects in side chains preorganize a protein main chain.


ABSTRACT: Preorganization is shown to endow a protein with extraordinary conformational stability. This preorganization is achieved by installing side-chain substituents that impose stereoelectronic and steric effects that restrict main-chain torsion angles. Replacing proline residues in (ProProGly)(7) collagen strands with 4-fluoroproline and 4-methylproline leads to the most stable known triple helices, having T ( m ) values that are increased by > 50 degrees C. Differential scanning calorimetry data indicate an entropic basis to the hyperstability, as expected from an origin in preorganization. Structural data at a resolution of 1.21 A reveal a prototypical triple helix with insignificant deviations to its main chain, even though 2/3 of the residues are nonnatural. Thus, preorganization of a main chain by subtle changes to side chains can confer extraordinary conformational stability upon a protein without perturbing its structure.

SUBMITTER: Shoulders MD 

PROVIDER: S-EPMC2818912 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Stereoelectronic and steric effects in side chains preorganize a protein main chain.

Shoulders Matthew D MD   Satyshur Kenneth A KA   Forest Katrina T KT   Raines Ronald T RT  

Proceedings of the National Academy of Sciences of the United States of America 20091231 2


Preorganization is shown to endow a protein with extraordinary conformational stability. This preorganization is achieved by installing side-chain substituents that impose stereoelectronic and steric effects that restrict main-chain torsion angles. Replacing proline residues in (ProProGly)(7) collagen strands with 4-fluoroproline and 4-methylproline leads to the most stable known triple helices, having T ( m ) values that are increased by > 50 degrees C. Differential scanning calorimetry data in  ...[more]

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