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Title: Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA)

Authors:
ORCiD logo; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); US National Institutes of Health (NIH)
OSTI Identifier:
1349117
DOE Contract Number:
AC02-05CH11231; AC02-06CH11357; AI076119; AI099284; AI100890; AI120860; GM103368; GM118012
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America; Journal Volume: 113; Journal Issue: 33
Country of Publication:
United States
Language:
ENGLISH
Subject:
X-ray crystallography; NRTIs; inhibitors; HIV-1 reverse transcriptase

Citation Formats

Salie, Zhe Li, Kirby, Karen A., Michailidis, Eleftherios, Marchand, Bruno, Singh, Kamalendra, Rohan, Lisa C., Kodama, Eiichi N., Mitsuya, Hiroaki, Parniak, Michael A., and Sarafianos, Stefan G. Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA). United States: N. p., 2016. Web. doi:10.1073/pnas.1605223113.
Salie, Zhe Li, Kirby, Karen A., Michailidis, Eleftherios, Marchand, Bruno, Singh, Kamalendra, Rohan, Lisa C., Kodama, Eiichi N., Mitsuya, Hiroaki, Parniak, Michael A., & Sarafianos, Stefan G. Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA). United States. doi:10.1073/pnas.1605223113.
Salie, Zhe Li, Kirby, Karen A., Michailidis, Eleftherios, Marchand, Bruno, Singh, Kamalendra, Rohan, Lisa C., Kodama, Eiichi N., Mitsuya, Hiroaki, Parniak, Michael A., and Sarafianos, Stefan G. 2016. "Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA)". United States. doi:10.1073/pnas.1605223113.
@article{osti_1349117,
title = {Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA)},
author = {Salie, Zhe Li and Kirby, Karen A. and Michailidis, Eleftherios and Marchand, Bruno and Singh, Kamalendra and Rohan, Lisa C. and Kodama, Eiichi N. and Mitsuya, Hiroaki and Parniak, Michael A. and Sarafianos, Stefan G.},
abstractNote = {},
doi = {10.1073/pnas.1605223113},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 33,
volume = 113,
place = {United States},
year = 2016,
month = 8
}
  • No abstract prepared.
  • Serine proteases play a crucial role in host-pathogen interactions. In the innate immune system of invertebrates, multi-domain protease inhibitors are important for the regulation of host-pathogen interactions and antimicrobial activities. Serine protease inhibitors, 9.3-kDa CrSPI isoforms 1 and 2, have been identified from the hepatopancreas of the horseshoe crab, Carcinoscorpius rotundicauda. The CrSPIs were biochemically active, especially CrSPI-1, which potently inhibited subtilisin (Ki=1.43 nM). CrSPI has been grouped with the non-classical Kazal-type inhibitors due to its unusual cysteine distribution. Here we report the crystal structure of CrSPI-1 in complex with subtilisin at 2.6 Å resolution and the results of biophysicalmore » interaction studies. The CrSPI-1 molecule has two domains arranged in an extended conformation. These two domains act as heads that independently interact with two separate subtilisin molecules, resulting in the inhibition of subtilisin activity at a ratio of 1:2 (inhibitor to protease). Each subtilisin molecule interacts with the reactive site loop from each domain of CrSPI-1 through a standard canonical binding mode and forms a single ternary complex. In addition, we propose the substrate preferences of each domain of CrSPI-1. Domain 2 is specific towards the bacterial protease subtilisin, while domain 1 is likely to interact with the host protease, Furin. Elucidation of the structure of the CrSPI-1: subtilisin (1:2) ternary complex increases our understanding of host-pathogen interactions in the innate immune system at the molecular level and provides new strategies for immunomodulation.« less
  • BMN 673, a novel PARP1/2 inhibitor in clinical development with substantial tumor cytotoxicity, forms extensive hydrogen-bonding and π-stacking in the nicotinamide pocket, with its unique disubstituted scaffold extending towards the less conserved edges of the pocket. These interactions might provide structural insight into the ability of BMN 673 to both inhibit catalysis and affect DNA-binding activity. Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2), which are involved in DNA damage response, are targets of anticancer therapeutics. BMN 673 is a novel PARP1/2 inhibitor with substantially increased PARP-mediated tumor cytotoxicity and is now in later-stage clinical development for BRCA-deficient breast cancers.more » In co-crystal structures, BMN 673 is anchored to the nicotinamide-binding pocket via an extensive network of hydrogen-bonding and π-stacking interactions, including those mediated by active-site water molecules. The novel di-branched scaffold of BMN 673 extends the binding interactions towards the outer edges of the pocket, which exhibit the least sequence homology among PARP enzymes. The crystallographic structural analyses reported here therefore not only provide critical insights into the molecular basis for the exceptionally high potency of the clinical development candidate BMN 673, but also new opportunities for increasing inhibitor selectivity.« less