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Molecular mechanism of respiratory syncytial virus fusion inhibitors

Molecular mechanism of respiratory syncytial virus fusion inhibitorsRespiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.

Nat Chem Biol. 2016 Feb;12(2):87-93. doi: 10.1038/nchembio.1982. Epub 2015 Dec 7.

 

Nature Publishing Group

© 2015 Macmillan Publishers Limited.

  Battles MB, Langedijk JP, Furmanova-Hollenstein P, Chaiwatpongsakorn S, Costello HM, Kwanten L, Vranckx L, Vink P, Jaensch S, Jonckers TH, Koul A, Arnoult E, Peeples ME, Roymans D, McLellan JS.

Another SBC Highlight:

Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892
Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana

Two-pore channels (TPCs) contain two copies of a Shaker-like six-transmembrane (6-TM) domain in each subunit.

 

Nature. 2016 Mar 10;531(7593):196-201. doi: 10.1038/nature16446. Epub 2015 Dec 21.

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SBC Announcements:

 

19-ID Pilatus Detector

SBC is pleased to announce the introduction of a Pilatus 3 X 6M detector into the User Program at beamline 19-ID.
Data collected by our users has been of outstanding quality.

 

 

 

19-BM Rebotic sample mounter available

A robot is now available for use at beamline 19-BM. The sample dewar accommodates ten Unipuck magazines; pins must be 18mm in length and use either SSRL or ALS bases. Experienced users may now request remote access to 19-BM when applying for beamtime.

 

 

 

ALSO: Please Be Aware...!

 

APS requests the Experimental Safety Approval Form (ESAF) be submitted at least seven days prior to your scheduled beamtime.

 

Failure to submit your ESAF in advance may result in delaying the beginning of your experiment.

 

Rapid Access Beamtime Available:

SBC Beamtime Request System

The on-line SBC Beamtime Request System allows users to view available beamtime on 19-ID and 19-BM, and to submit a request for rapid beamtime allocation.

Beamtime is available to the research community via a peer reviewed proposal system; it is supported by the U.S. Department of Energy, Office of Biological and Environmental Research.

Current Beamline Statistics:

APS PDB Depositions from BioSync
SBC Sector 19 2014 2015 2016 TOTAL
ID BM ID BM ID BM
PDB Depositions 262 35 211 22 22 04 4695

APS Publications Database:

Publications Total
SBC-CAT Publication List: 19-ID 1388
SBC-CAT Publication List: 19-BM 517
SBC-CAT Publication List: ALL
APS Publications Database

MCSG / APCF Announcements:

 

Beginning August 01, 2015 the Midwest Center for Structural Genomics (MCSG) will start accepting applications for access to the MCSG User Resource.

 

MCSG's structure determination platform is well established, and combines technologies, robotics and expertise for gene cloning, protein production, and crystallization, as well as biochemical and biophysical characterization.

 

For further information, please contact Andrzej Joachimiak.

 

Future Meetings:

 

APS/CNM Users Meeting

May 09-12, 2016

Advanced Photon Source, Argonne National Laboratory; Argonne, IL

 

Protein Society: 30th Anniversary Symposium

July 16-19, 2016

Hyatt Regency Baltimore; Baltimore MD

 

American Crystallographic Association, 2016

July 22-26, 2016

Downtown Sheraton Hotel; Denver CO

 

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