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Computational design of an integrin I domain stabilized in the open high affinity conformation

Shimaoka, Motomu and Shifman, Julia M. and Jing, Hua and Takagi, Junichi and Mayo, Stephen L. and Springer, Timothy A. (2000) Computational design of an integrin I domain stabilized in the open high affinity conformation. Nature Structural Biology, 7 (8). pp. 674-678. ISSN 1072-8368 . http://www.nature.com/doifinder/10.1038/77978

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Abstract

We have taken a computational approach to design mutations that stabilize a large protein domain of approximately 200 residues in two alternative conformations. Mutations in the hydrophobic core of the αMβ2 integrin I domain were designed to stabilize the crystallographically defined open or closed conformers. When expressed on the cell surface as part of the intact heterodimeric receptor, binding of the designed open and closed I domains to the ligand iC3b, a form of the complement component C3, was either increased or decreased, respectively, compared to wild type. Moreover, when expressed in isolation from other integrin domains using an artificial transmembrane domain, designed open I domains were active in ligand binding, whereas designed closed and wild type I domains were inactive. Comparison to a human expert designed open mutant showed that the computationally designed mutants are far more active. Thus, computational design can be used to stabilize a molecule in a desired conformation, and conformational change in the I domain is physiologically relevant to regulation of ligand binding.


Item Type:Article
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http://dx.doi.org/10.1038/77978 DOIUNSPECIFIED
http://www.nature.com/doifinder/10.1038/77978PublisherUNSPECIFIED
Additional Information:© 2000 Nature America Inc. Received 13 April, 2000; accepted 20 June, 2000. We thank M. Ferzly for technical assistance. This work was supported by the NIH.
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Funding AgencyGrant Number
NIHUNSPECIFIED
Subject Keywords:Transfection; Protein Binding; Complement C3b; Thermodynamics; Integrins; Amino Acid Substitution; Computer Simulation; Humans; Dimerization; Models: Molecular; Cell Line; Protein Engineering; Protein Structure: Tertiary; Mutation; Binding Sites; Structure-Activity Relationship; Protein Structure: Secondary; Ligands
Record Number:CaltechAUTHORS:20110620-160434458
Persistent URL:http://www.nature.com/doifinder/10.1038/77978
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:24128
Collection:CaltechAUTHORS
Deposited By: Marie Ary
Deposited On:15 Sep 2011 17:05
Last Modified:15 Sep 2011 17:05

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