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Inhibition of RAS function through targeting an allosteric regulatory site

inhibition of ras function through targeting an allosteric regulatory siteRAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here we describe a functionally critical region, located outside the effector lobe of RAS, that can be targeted for inhibition. We developed NS1, a synthetic binding protein (monobody) that bound with high affinity to both GTP- and GDP-bound states of H-RAS and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H-RAS- and K-RAS- mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1. NS1 bound the α4-β6-α5 region of RAS, which disrupted RAS dimerization and nanoclustering and led to blocking of CRAF–BRAF heterodimerization and activation. These results establish the importance of the α4-β6-α5 interface in RAS-mediated signaling and define a previously unrecognized site in RAS for inhibiting RAS function.

Nat Chem Biol. 2017 Jan;13(1):62-68.
doi: 10.1038/nchembio.2231. Epub 2016 Nov 7.

 

© Copyright 2017 Macmillan Publishers Limited

  Spencer-Smith R, Koide A, Zhou Y, Eguchi RR, Sha F, Gajwani P, Santana D, Gupta A, Jacobs M, Herrero-Garcia E, Cobbert J, Lavoie H, Smith M, Rajakulendran T, Dowdell E, Okur MN, Dementieva I, Sicheri F, Therrien M, Hancock JF, Ikura M, Koide S, O'Bryan JP.

Another SBC Highlight:

Crystal structures of the human elongation factor eEFSec suggest a non-canonical mechanism for selenocysteine incorporation
Non-classical transpeptidases yield insight into new antibacterials

 

 

Nat Chem Biol. 2017 Jan;13(1):54-61.
doi: 10.1038/nchembio.2237.
Epub 2016 Nov 7.

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SBC Announcements:

 

19-ID Pilatus Detector

 

SBC has implemented 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 Robotic sample mounter available

 

A robot is 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.

 

 

SBC Staff Hosting Changes

 

SBC staff are now available for User Support between the hours of 8:00am and 10:pm.

 

 

 

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.

 

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If you have any suggestions or comments, please feel free to e-mail us.

 

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 2015 2016 2017 TOTAL
ID BM ID BM ID BM
PDB Depositions 263 32 148 24 5 3 4913

APS Publications Database:

Publications Total
SBC-CAT Publication List: 19-ID 1459
SBC-CAT Publication List: 19-BM 528
SBC-CAT Publication List: ALL
APS Publications Database

MCSG / APCF Announcements:

 

The Midwest Center for Structural Genomics (MCSG) is 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:

 

61st Annual Meeting of the Biophysical Society (with new Cryo-EM Subgroup meeting)

February 11-15, 2017

New Orleans; Louisiana, USA

 

XXIII West Coast Protein Crystallography Workshop

March 19-22, 2017

Pacific Grove; California, USA

 

2017 Annual Meeting of the American Crystallographic Association

May 26-30, 2017

New Orleans; Louisiana, USA

 

SBC Beamline Phone Numbers:

Phone Location Number
19-ID Beamline Control Station 630-252-9823
19-ID Beamline Cordless Phone 630-252-0569
19-ID Beamline Inside D-Hutch 630-252-1819
 
19-BM Beamline Control Station 630-252-9833
19-BM Beamline Cordless Phone 630-252-0568
19-BM Beamline Inside D-Hutch 630-252-1719