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Structural integration in hypoxia-inducible factors

Hypoxia-inducible factor with DNAThe hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-α and ARNT (also called HIF-1β) subunits. Here we describe crystal structures for each of mouse HIF-2α–ARNT and HIF-1α–ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2α–ARNT and HIF-1α–ARNT, wherein ARNT spirals around the outside of each HIF-α subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-α mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.

Nature; published online 05 August 2015.

DOI: 10.1038/nature14883

©2015 Macmillan Publishers Limited. All rights reserved.

  Dalei Wu, Nalini Potluri, Jingping Lu, Youngchang Kim & Fraydoon Rastinejad.

Another SBC Highlight:

Figure_05
Functional Diversity of Haloacid Dehalogenase Superfamily Phosphatase from Saccharomyces cerevisiae

The haloacid dehalogenase (HAD)-like enzymes comprise a large superfamily of phosphohydrolases present in all organisms. The Saccharomyces cerevisiae genome encodes at least 19 soluble HADs, including 10 uncharacterized proteins. Here, we biochemically characterized 13 yeast phosphatases from the HAD superfamily, which includes both specific and promiscuous enzymes active against various phosphorylated metabolites and peptides with several HADs implicated in detoxification of phosphorylated compounds and pseudouridine.

 

J Biol Chem. 2015 Jul 24;290(30):18678-98. doi: 10.1074/jbc.M115.657916. Epub 2015 Jun 12.

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Future Meetings:

 

Beyond Rg: Materials SAXS Short Course 2015

October 12-16, 2015

Advanced Photon Source, Argonne National Laboratory; Argonne, IL

 

Biophysical Society Annual Meeting

February 27 - March 02, 2016

Los Angeles Convention Center; Los Angeles, CA

 

APS/CNM Users Meeting

May 09-12, 2016

Advanced Photon Source, Argonne National Laboratory; Argonne, IL

 

American Crystallographic Association, 2016

July 22-26, 2016

Downtown Sheraton Hotel; Denver CO

 

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 2013 2014 2015 TOTAL
ID BM ID BM ID BM
PDB Depositions 238 49 252 33 75 10 4510

APS Publications Database:

Publications Total
SBC-CAT Publication List: 19-ID 1465
SBC-CAT Publication List: 19-BM 551
SBC-CAT Publication List: ALL 1816
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.

 

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