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Title: Fragment-based identification of determinants of conformational and spectroscopic change at the ricin active site

Abstract

We found that amide ligands can bind weakly but specifically to the ricin active site, producing significant shifts in positions of the critical active site residues Arg180 and Tyr80. These results indicate that fragment-based drug discovery methods are capable of identifying minimal bonding determinants of active-site side-chain rearrangements and the mechanistic origins of spectroscopic shifts. Our results suggest that tryptophan fluorescence provides a sensitive probe for the geometric relationship of arginine-tryptophan pairs, which often have significant roles in protein function. Using the unusual characteristics of the RTA system, we measured the still controversial thermodynamic changes of site-specific urea binding to a protein, results that are relevant to understanding the physical mechanisms of protein denaturation.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
960079
Report Number(s):
BNL-83065-2009-JA
TRN: US201016%%1223
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: BMC Structural Biology; Journal Volume: 7
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; AMIDES; BONDING; FLUORESCENCE; PROTEIN DENATURATION; PROTEINS; RESIDUES; THERMODYNAMICS; TRYPTOPHAN; UREA; LIGANDS; national synchrotron light source

Citation Formats

Carra,J., McHugh, C., Mulligan, S., Machiesky, L., Soares, A., and Millard, C. Fragment-based identification of determinants of conformational and spectroscopic change at the ricin active site. United States: N. p., 2007. Web. doi:10.1186/1472-6807-7-72.
Carra,J., McHugh, C., Mulligan, S., Machiesky, L., Soares, A., & Millard, C. Fragment-based identification of determinants of conformational and spectroscopic change at the ricin active site. United States. doi:10.1186/1472-6807-7-72.
Carra,J., McHugh, C., Mulligan, S., Machiesky, L., Soares, A., and Millard, C. Mon . "Fragment-based identification of determinants of conformational and spectroscopic change at the ricin active site". United States. doi:10.1186/1472-6807-7-72.
@article{osti_960079,
title = {Fragment-based identification of determinants of conformational and spectroscopic change at the ricin active site},
author = {Carra,J. and McHugh, C. and Mulligan, S. and Machiesky, L. and Soares, A. and Millard, C.},
abstractNote = {We found that amide ligands can bind weakly but specifically to the ricin active site, producing significant shifts in positions of the critical active site residues Arg180 and Tyr80. These results indicate that fragment-based drug discovery methods are capable of identifying minimal bonding determinants of active-site side-chain rearrangements and the mechanistic origins of spectroscopic shifts. Our results suggest that tryptophan fluorescence provides a sensitive probe for the geometric relationship of arginine-tryptophan pairs, which often have significant roles in protein function. Using the unusual characteristics of the RTA system, we measured the still controversial thermodynamic changes of site-specific urea binding to a protein, results that are relevant to understanding the physical mechanisms of protein denaturation.},
doi = {10.1186/1472-6807-7-72},
journal = {BMC Structural Biology},
number = ,
volume = 7,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}