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

Journal Article · · ChemMedChem
 [1];  [2];  [2];  [1];  [3];  [3];  [3];  [4];  [4]
  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)
+ Show Author Affiliations

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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-05CH11231; 5R01EB005217; GR/S19929/01
OSTI ID:
1257822
Journal Information:
ChemMedChem, Vol. 9, Issue 10; ISSN 1860-7179
Publisher:
ChemPubSoc EuropeCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 17 works
Citation information provided by
Web of Science

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Cited By (3)

Human platelets repurposed as vehicles forin vivoimaging of myeloma xenotransplants journal March 2016
The Potential of Indonesian Heterobranchs Found around Bunaken Island for the Production of Bioactive Compounds journal December 2017
Development of a novel inducer of protein–protein interactions based on aplyronine A journal January 2018

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Actin
macrolide analogs
structural biology
chemical synthesis*