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Important role of hydrogen bonds in the structurally polarized transition state for folding of the src SH3 domain

Nature Structural Biology volume 5, pages 714–720 (1998)Cite this article

Abstract

Experimental and theoretical studies on the folding of small proteins such as the chymotrypsin inhibitor 2 (CI-2) and the P22 Arc repressor suggest that the folding transition state is an expanded version of the native state with most interactions partially formed. Here we report that this picture does not hold generally: a hydrogen bond network involving two β-turns and an adjacent hydrophobic cluster appear to be formed in the folding transition state of the src SH3 domain, while the remainder of the polypeptide chain is largely unstructured. Comparison with data on other small proteins suggests that this structural polarization is a consequence of the topology of the SH3 domain fold. The non-uniform distribution of structure in the folding transition state provides a challenging test for computational models of the folding process.

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Acknowledgements

We thank M. Eck for providing us with the atomic coordinates of src tyrosine kinase prior to submitting them in the Brookhaven protein data bank, Q. Yi for mass spectrometry analysis of all the SH3 mutants, J. Onuchic and members of the Baker group for useful comments on the manuscript, and L. Serrano and coworkers for sharing their manuscript on the spectrin folding transition state prior to publication. This work was supported by a grant from the Office of Naval Research and Young Investigator awards to D. B. from the NSF and the Packard Foundation.

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Author notes

  1. Viara P. Grantcharova and David S. Riddle: Both of these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, University of Washington, Seattle, 98195, Washington, USA

    Viara P. Grantcharova, David S. Riddle, Jed V. Santiago & David Baker

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  1. Viara P. Grantcharova
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  2. David S. Riddle
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Correspondence to David S. Riddle.

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Grantcharova, V., Riddle, D., Santiago, J. et al. Important role of hydrogen bonds in the structurally polarized transition state for folding of the src SH3 domain. Nat Struct Mol Biol 5, 714–720 (1998). https://doi.org/10.1038/1412

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