Document Detail


Computational design of receptors for an organophosphate surrogate of the nerve agent soman.
MedLine Citation:
PMID:  15148405     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We report the computational design of soluble protein receptors for pinacolyl methyl phosphonic acid (PMPA), the predominant hydrolytic product of the nerve agent soman. Using recently developed computational protein design techniques, the ligand-binding pockets of two periplasmic binding proteins, glucose-binding protein and ribose-binding protein, were converted to bind PMPA instead of their cognate sugars. The designs introduce 9-12 mutations in the parent proteins. Twelve of 20 designs tested exhibited PMPA-dependent changes in emission intensity of a fluorescent reporter with affinities between 45 nM and 10 microM. The contributions to ligand binding by individual residues were determined in two designs by alanine-scanning mutagenesis, and are consistent with the molecular models. These results demonstrate that designed receptors with radically altered binding specificities and affinities that rival or exceed those of the parent proteins can be successfully predicted. The designs vary in parent scaffold, sequence diversity, and orientation of docked ligand, suggesting that the number of possible solutions to the design problem is large and degenerate. This observation has implications for the genesis of biological function by random processes. The designed receptors reported here may have utility in the development of fluorescent biosensors for monitoring nerve agents.
Authors:
Malin Allert; Shahir S Rizk; Loren L Looger; Homme W Hellinga
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2004-05-17
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  101     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-05-26     Completed Date:  2004-07-09     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7907-12     Citation Subset:  IM    
Affiliation:
Departments of Biochemistry and Pharmacology and Molecular Cancer Biology, Box 3711, Duke University Medical Center, Durham, NC 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
Binding Sites
Biosensing Techniques
Computer Simulation*
Drug Design*
Ligands
Models, Molecular
Mutagenesis / genetics
Protein Binding
Receptors, Cell Surface / chemistry,  genetics*,  metabolism*
Soman / analogs & derivatives*,  metabolism*
Substrate Specificity
Thermodynamics
Chemical
Reg. No./Substance:
0/Ligands; 0/Receptors, Cell Surface; 96-64-0/Soman; 99YXE507IL/pinacolyl methylphosphonic acid
Comments/Corrections

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