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Economy in Protein Design:  Evolution of a Metal-Independent ββα Motif Based on the Zinc Finger Domains

Struthers, Mary D. and Cheng, Richard P. and Imperiali, Barbara (1996) Economy in Protein Design:  Evolution of a Metal-Independent ββα Motif Based on the Zinc Finger Domains. Journal of the American Chemical Society, 118 (13). pp. 3073-3081. ISSN 0002-7863. https://resolver.caltech.edu/CaltechAUTHORS:20180517-161205709

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Abstract

An iterative design process involving the synthesis and structural analyses of five polypeptides patterned after the zinc finger domains is described. This process has led to the development of a metal-independent folded ββα motif, BBA1. In contrast to the zinc fingers and other naturally occurring peptides of similar size, this small monomeric structure folds without the assistance of metal cation ligation or disulfide bridges. To probe the effect of metal binding on the secondary and tertiary structure of peptides throughout the design process, a non-standard amino acid 3-(1,10-phenanthrol-2-yl)-l-alanine (Fen) was incorporated and its unique chromophore utilized for circular dichroism (CD) analysis. Advanced designs were analyzed by both CD and 2D NMR. The solution structure of BBA1 was determined using NOE restrained simulated annealing. The average RMSD for the backbone atoms of residues 1−22 is 0.9 ± 0.3 Å. Analysis of the resulting structure reveals that the α-helix and β-hairpin are associated via a well-defined hydrophobic core including several key hydrophobic residues. A key design feature of BBA1 is the utilization of a type II‘ reverse turn to promote β-hairpin formation; a control peptide, in which the β-turn of BBA1 was changed from a type II‘ to a type II, lacks tertiary structure. Thus the effects of the turn type on the three-dimensional structure of this motif are dramatic. BBA1, a 23-residue mixed α/β motif, defines a new lower limit for the size of an independently folded polypeptide with native structure.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/ja954014uDOIArticle
Additional Information:© 1996 American Chemical Society. Received November 29, 1995. Publication Date (Web): April 3, 1996. This work was supported by NSF Grant CHE-910445, a Parsons Foundation predoctoral fellowship (to M.D.S.), an NIH traineeship to R.P.C., and a Camille and Henry Dreyfus Teacher Scholar Award (to B.I.). We gratefully acknowledge the Dorothy Chandler, Camilla Chandler Frost Laboratory in Biology at Caltech for use of the Varian Unity Plus 600 NMR spectrometer.
Funders:
Funding AgencyGrant Number
NSFCHE-910445
Ralph M. Parsons FoundationUNSPECIFIED
NIH Predoctoral FellowshipUNSPECIFIED
Camille and Henry Dreyfus FoundationUNSPECIFIED
Issue or Number:13
Record Number:CaltechAUTHORS:20180517-161205709
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180517-161205709
Official Citation:Economy in Protein Design:  Evolution of a Metal-Independent ββα Motif Based on the Zinc Finger Domains. Mary D. Struthers, Richard P. Cheng, and Barbara Imperiali. Journal of the American Chemical Society 1996 118 (13), 3073-3081. DOI: 10.1021/ja954014u
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:86444
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 May 2018 16:54
Last Modified:03 Oct 2019 19:43

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