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Title: Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues

Abstract

The actin filament-binding and filament-severing activities of the aplyronine, kabiramide, and reidispongiolide families of marine macrolides are located within the hydrophobic tail region of the molecule. Two synthetic tail analogues of aplyronine C (SF-01 and GC-04) are shown to bind to G-actin with dissociation constants of (285±33) and (132±13) nM, respectively. The crystal structures of actin complexes with GC-04, SF-01, and kabiramide C reveal a conserved mode of tail binding within the cleft that forms between subdomains (SD) 1 and 3. Our studies support the view that filament severing is brought about by specific binding of the tail region to the SD1/SD3 cleft on the upper protomer, which displaces loop-D from the lower protomer on the same half-filament. With previous studies showing that the GC-04 analogue can sever actin filaments, it is argued that the shorter complex lifetime of tail analogues with F-actin would make them more effective at severing filaments compared with plasma gelsolin. In conclusion, structure-based analyses are used to suggest more reactive or targetable forms of GC-04 and SF-01, which may serve to boost the capacity of the serum actin scavenging system, to generate antibody conjugates against tumor cell antigens, and to decrease sputum viscosity in childrenmore » with cystic fibrosis.« less

Authors:
 [1];  [2];  [2];  [1];  [3];  [3];  [3];  [4];  [4]
+ Show Author Affiliations
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  2. Univ. of California, Berkeley, CA (United States)
  3. University Chemical Laboratory, Cambridge (United Kingdom)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1257822
Grant/Contract Number:  
AC02-05CH11231; 5R01EB005217; GR/S19929/01
Resource Type:
Accepted Manuscript
Journal Name:
ChemMedChem
Additional Journal Information:
Journal Volume: 9; Journal Issue: 10; Journal ID: ISSN 1860-7179
Publisher:
ChemPubSoc Europe
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Actin; macrolide analogs; structural biology; chemical synthesis*

Citation Formats

Pereira, Jose H., Petchprayoon, Chutima, Hoepker, Alexander C., Moriarty, Nigel W., Fink, Sarah J., Cecere, Giuseppe, Paterson, Ian, Adams, Paul D., and Marriott, Gerard. Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues. United States: N. p., 2014. Web. doi:10.1002/cmdc.201402150.
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Pereira, Jose H., Petchprayoon, Chutima, Hoepker, Alexander C., Moriarty, Nigel W., Fink, Sarah J., Cecere, Giuseppe, Paterson, Ian, Adams, Paul D., & Marriott, Gerard. Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues. United States. https://doi.org/10.1002/cmdc.201402150
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Pereira, Jose H., Petchprayoon, Chutima, Hoepker, Alexander C., Moriarty, Nigel W., Fink, Sarah J., Cecere, Giuseppe, Paterson, Ian, Adams, Paul D., and Marriott, Gerard. Tue . "Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues". United States. https://doi.org/10.1002/cmdc.201402150. https://www.osti.gov/servlets/purl/1257822.
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@article{osti_1257822,
title = {Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues},
author = {Pereira, Jose H. and Petchprayoon, Chutima and Hoepker, Alexander C. and Moriarty, Nigel W. and Fink, Sarah J. and Cecere, Giuseppe and Paterson, Ian and Adams, Paul D. and Marriott, Gerard},
abstractNote = {The actin filament-binding and filament-severing activities of the aplyronine, kabiramide, and reidispongiolide families of marine macrolides are located within the hydrophobic tail region of the molecule. Two synthetic tail analogues of aplyronine C (SF-01 and GC-04) are shown to bind to G-actin with dissociation constants of (285±33) and (132±13) nM, respectively. The crystal structures of actin complexes with GC-04, SF-01, and kabiramide C reveal a conserved mode of tail binding within the cleft that forms between subdomains (SD) 1 and 3. Our studies support the view that filament severing is brought about by specific binding of the tail region to the SD1/SD3 cleft on the upper protomer, which displaces loop-D from the lower protomer on the same half-filament. With previous studies showing that the GC-04 analogue can sever actin filaments, it is argued that the shorter complex lifetime of tail analogues with F-actin would make them more effective at severing filaments compared with plasma gelsolin. In conclusion, structure-based analyses are used to suggest more reactive or targetable forms of GC-04 and SF-01, which may serve to boost the capacity of the serum actin scavenging system, to generate antibody conjugates against tumor cell antigens, and to decrease sputum viscosity in children with cystic fibrosis.},
doi = {10.1002/cmdc.201402150},
journal = {ChemMedChem},
number = 10,
volume = 9,
place = {United States},
year = {Tue Jul 22 00:00:00 EDT 2014},
month = {Tue Jul 22 00:00:00 EDT 2014}
}
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