Imperial College London

ProfessorStephenCurry

Faculty of Natural SciencesDepartment of Life Sciences

Professor of Structural Biology
 
 
 
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Contact

 

+44 (0)20 7594 7632s.curry Website

 
 
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Assistant

 

Mrs Jacalyn Murphy +44 (0)20 7594 1919

 
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Location

 

404ASir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Nishi:2011:10.1074/jbc.M110.208926,
author = {Nishi, K and Ono, T and Nakamura, T and Fukunaga, N and Izumi, M and Watanabe, H and Suenaga, A and Maruyama, T and Yamagata, Y and Curry, S and Otagiri, M},
doi = {10.1074/jbc.M110.208926},
journal = {Journal of Biological Chemistry},
pages = {14427--14434},
title = {Structural Insights into Differences in Drug-binding Selectivity between Two Forms of Human α1-Acid Glycoprotein Genetic Variants, the A and F1*S Forms},
url = {http://dx.doi.org/10.1074/jbc.M110.208926},
volume = {286},
year = {2011}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - Human α(1)-acid glycoprotein (hAGP) in serum functions as a carrier of basic drugs. In most individuals, hAGP exists as a mixture of two genetic variants, the F1S and A variants, which bind drugs with different selectivities. We prepared a mutant of the A variant, C149R, and showed that its drug-binding properties were indistinguishable from those of the wild type. In this study, we determined the crystal structures of this mutant hAGP alone and complexed with disopyramide (DSP), amitriptyline (AMT), and the nonspecific drug chlorpromazine (CPZ). The crystal structures revealed that the drug-binding pocket on the A variant is located within an eight-stranded β-barrel, similar to that found in the F1S variant and other lipocalin family proteins. However, the binding region of the A variant is narrower than that of the F1S variant. In the crystal structures of complexes with DSP and AMT, the two aromatic rings of each drug interact with Phe-49 and Phe-112 at the bottom of the binding pocket. Although the structure of CPZ is similar to those of DSP and AMT, its fused aromatic ring system, which is extended in length by the addition of a chlorine atom, appears to dictate an alternative mode of binding, which explains its nonselective binding to the F1S and A variant hAGPs. Modeling experiments based on the co-crystal structures suggest that, in complexes of DSP, AMT, or CPZ with the F1S variant, Phe-114 sterically hinders interactions with DSP and AMT, but not CPZ.
AU - Nishi,K
AU - Ono,T
AU - Nakamura,T
AU - Fukunaga,N
AU - Izumi,M
AU - Watanabe,H
AU - Suenaga,A
AU - Maruyama,T
AU - Yamagata,Y
AU - Curry,S
AU - Otagiri,M
DO - 10.1074/jbc.M110.208926
EP - 14434
PY - 2011///
SN - 1083-351X
SP - 14427
TI - Structural Insights into Differences in Drug-binding Selectivity between Two Forms of Human α1-Acid Glycoprotein Genetic Variants, the A and F1S Forms
T2 - Journal of Biological Chemistry
UR - http://dx.doi.org/10.1074/jbc.M110.208926
UR - http://hdl.handle.net/10044/1/33342
VL - 286
ER -