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Resistance to Enediyne Antitumor Antibiotics by Sequestration

RCC2 is a novel p53 target in suppressing metastasisThe enediynes, microbial natural products with extraordinary cytotoxicities, have been translated into clinical drugs. Two self-resistance mechanisms are known in the enediyne producers-apoproteins for the nine-membered enediynes and self-sacrifice proteins for the ten-membered enediyne calicheamicin. Here we show that: (1) tnmS1, tnmS2, and tnmS3 encode tiancimycin (TNM) resistance in its producer Streptomyces sp. CB03234, (2) tnmS1, tnmS2, and tnmS3 homologs are found in all anthraquinone-fused enediyne producers, (3) TnmS1, TnmS2, and TnmS3 share a similar β barrel-like structure, bind TNMs with nanomolar KD values, and confer resistance by sequestration, and (4) TnmS1, TnmS2, and TnmS3 homologs are widespread in nature, including in the human microbiome. These findings unveil an unprecedented resistance mechanism for the enediynes. Mechanisms of self-resistance in producers serve as models to predict and combat future drug resistance in clinical settings. Enediyne-based chemotherapies should now consider the fact that the human microbiome harbors genes encoding enediyne resistance.

Cell Chem Biol. 2018 May 29.

pii: S2451-9456(18)30183-1.

doi: 10.1016/j.chembiol.2018.05.012

  Chang CY, Yan X, Crnovcic I, Annaval T, Chang C, Nocek B, Rudolf JD, Yang D, Hindra, Babnigg G, Joachimiak A, Phillips GN Jr, Shen B.

Another SBC Highlight:

DNA Sequence Recognition of Human CXXC Domains and Their Structural Determinants

Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor

 

 

Nat Commun. 2018 Jan 30;9(1):425.
doi: 10.1038/s41467-017-02013-1.

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SBC Announcements:

 

New Oxford Cryostream 800 Series now available on both 19-ID and 19-BM.

 

Rigaku Actor Robot, with heated end effector, upgraded on 19-ID.

 

A sample-mounting robot is available for use at beamline 19-BM. The 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.

 

 

ESAF Requirements:

 

When completing your Experimental Safety Approval Form (ESAF), please include the following in your experimental description:

 

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

 

Failure to submit your ESAF according to this schedule may result in delaying the beginning of your experiment.

 

 

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

 

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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 2016 2017 2018 TOTAL
ID BM ID BM ID BM
PDB Depositions 232 29 232 45 58 13 5342

APS Publications Database:

Publications Total
SBC-CAT Publication List: 19-ID 1596
SBC-CAT Publication List: 19-BM 561
SBC-CAT Publication List: ALL
APS Publications Database

MCSG / APCF Announcements:

 

Access to the Advanced Protein Characterization Facility (APCF), housing the Midwest Center for Structural Genomics (MCSG), requires successful completion of an ANL Guest/Joint Appointee application, procurement of an Argonne domain account, and currently valid requisite training for building #446 and ANL.

 

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.

 

 

 

SBC Beamline Phone Numbers:

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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