Category "Structural Biology"

WEBINAR DETAILS

Recorded on: Tuesday, January 24, 2017
Duration: 60 minutes
Featured Speaker: Douglas R. Davies, Senior Manager of Structural Biology, Beryllium Discovery Corp.

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This webinar will discuss the use of ligand-observe NMR techniques for rapid and efficient fragment screening of viral targets. Fragment screening was performed on two different viral proteins, an H1N1 Influenza A virus polymerase acid protein C-terminal domain (PA-CTD) and the Ebola virus matrix protein VP30 as part of a structural genomics consortium which targets infectious diseases. The influenza virus PA-CTD is part of the heterotrimeric viral RNA-dependent RNA polymerase involved in genome replication, whereas the Ebola virus VP30 protein is a phosphoprotein which associates with the nucleocapsid protein and is essential for viral transcription initiation.

In each case, the strategy was to target a protein-protein interface rather than an enzymatic active site. Interestingly, the majority of hits for the influenza A virus PA-CTD screen bind to a surface exposed site located near the viral RNA loading site rather than the expected PB1 N-terminus binding site which is a computational hot spot. Crystal structures of initial hits and follow on analogue-by-catalogue compounds were obtained. For the Ebola virus VP30 screen, VP30 was screened from both the 2013-2015 Zaire outbreak as well as the related Marburg virus VP30 in an effort to identify fragments which can target divergent viral VP30 strains. All of this work has been done as part of the Seattle Structural Genomics Center for Infectious Disease (SSGCID), a structural genomics consortium funded by the National Institute for Allergy and Infectious Diseases (NIAID).

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Doug Davies Senior Manager Structural BiologyAbout Douglas R. Davies, Senior Manager of Structural Biology, Beryllium Discovery Corp.
Over the past twenty years, some of Douglas’ work has focused on structural studies of functional nucleic acids and nucleic-acid modifying enzymes. His graduate thesis work at the University of Wisconsin-Madison involved the first structures of Tn5transposase. As a postdoctoral fellow at the University of Washington, Douglas studied the DNA repair enzyme Tyrosyl DNA Phosphodiersterase (Tdp1), elucidating the first crystal structures and verifying the proposed mechanism of action. During the past 10 years at Beryllium, he has applied these experiences to a number of DNA aptamer diagnostics and potential therapeutics (SOMAmers) as well as DNA Polymerase C from Geobacillus kaustophilus. Douglas is the lead crystallographer for 77 crystal structures in the Protein Data Bank and has published 28 peer-reviewed journal articles.

 

Please join us on Tuesday, May 31st 2016 at 11AM EDT for a webinar led by Dr. Douglas  R. Davies, Sr. Manager of Structural Biology at Beryllium Discovery.

This webinar will highlight unique attributes of SOMAmers but also discuss similarities between aptamers and antibodies from the standpoints of and target protein recognition and shape complementarity.

Register for free here.

Aptamers are nucleic acids that fold into a well-defined three-dimensional structure and exhibit high affinity for a specific target molecule. Many aptamers are simple single-stranded DNA or RNA, although the incorporation of chemical diversity-enhancing side chains has led to the development of “slow off-rate modified aptamers” (SOMAmers). Investigators at Beryllium and SomaLogic, Inc. have collaborated to elucidate three crystal structures of proteins in complex with SOMAmers. The SOMAmer structures are distinctive members of the ensemble of sixteen aptamer-protein complex structures that have been reported to date.

About Beryllium

Beryllium is shaping the future of collaborative drug discovery. Our proven teams of drug discovery professionals are passionate about unlocking the therapeutic potential of both genetically- and clinically-validated drug targets, as well as developing new therapeutic modalities. We work in partnership with our clients to address the most difficult scientific and business challenges facing drug discovery, and to ultimately enable transformational health care outcomes.

We enable novel drug discovery by applying structural and functional biology-centric processes and platforms. Our goal is to deliver validated starting points for drug development programs, and our teams of pharma industry veterans are applying multidisciplinary knowledge to tackle the most promising therapeutic targets.

 

“We are excited to tell the story of one of the Beryllium collaborations on tuberculosis targets next week at PEGS.  As many in the anti-infectives therapeutics realm have realized, less than 10% of the disease-relevant proteome of mycobacterium tuberculosis has been successfully solved at the level of high dimensional 3-D structure.  Beryllium teamed up with the Seattle Structural Genomics Center for Infectious Disease (SSGCID) and others to address the question “Can we increase the breadth of structural insights within the disease-relevant protein group in the pathogen M. tuberculosis?”.   Accordingly, we demonstrate the utility of homologue rescue in this study- essentially applying a system for using surrogate sequences of the active sites from other mycobacteria – to establish a relationship between sequence identity and active site structural similarity between homologues.  This system applied to 179 potential tuberculosis drug targets increased the structural coverage more than 3-fold!”

MCL1 is one of the top-ten most amplified genes in all of human cancer and is vital to tumor development and cancer progression. Although MCL1 is a well-known cancer drug target, obtaining ligand-bound crystal structures has proven to be difficult.   In collaboration with the Broad Institute of MIT and Harvard, Scientists at Beryllium developed a robust crystallographic platform for MCL1 that uses a combination of fusion protein and sequence engineering.   Unlike previously available structures based on ligand dependent interactions, the new methods allow for systematic screening against MCL1 and opens the door to structure based drug design. 

Clifton et al describe their work in their recent PLOS One publication, where the first Apo and fragment bound x-ray structures of MCL1 are described. These structures provide important breakthroughs for MCL1 drug discovery by providing insight into conformational changes that occur upon ligand binding.  In addition, the approach allows for the observation of ligand binding to MCL1 in a non-ligand dependent manner.

About Beryllium:

Using our biology-first, target-centric approach and established platforms, we provide research services and engage in collaborations with commercial and academic partners.   Our teams of experienced scientists work closely with our clients to help manage and advance their goals by complementing their capabilities and resources.

BEDFORD, Mass. – February 12, 2015 – In this week’s issue of Science, researchers at Gilead Sciences, Inc. (Nasdaq:GILD) and Beryllium reveal new details about how the hepatitis C virus (HCV) replicates its genome. HCV is estimated to affect 150-200 million people worldwide and is the major cause of liver transplantation in the US. HCV uses RNA as genetic material which must be replicated in order to propagate the viral infection. Appleby et al. determined high resolution X-ray crystal structures of the HCV polymerase during the process of RNA replication, shedding light on the replication complex after 15 years of speculation. These molecular snap-shots unveil the NS5B catalytic mechanism in successive steps from the opening of the fist-like polymerase through the rapid RNA polymerization stage known as elongation. “For the first time we can see at the atomic level how the HCV polymerase interacts with the genomic RNA template, replicating RNA, and nucleotide substrates,” said corresponding author Thomas Edwards of Beryllium.

Sofosbuvir acts during the elongation stage of HCV genomic replication, where the nucleotide triphosphate metabolite of the drug is incorporated into the growing RNA strand and terminates replication. The structural data presented by Appleby et al.demonstrate how the HCV polymerase recognizes sofosbuvir in a manner distinct from either native substrates or other nucleotide-based therapies.

“These structures advance our understanding of how an important member of the Flaviviridae family of viruses replicates genomic RNA,” said William Lee, Senior Vice President of Research at Gilead Sciences. “This information will be useful in identifying replication inhibitors of other pathogenic viruses in this family responsible for human diseases.”

Copies of the Science paper may be obtained from the AAAS Office of Public Programs. Please call +1-202-326-6440 or email scipak@aaas.org.


About Beryllium

Beryllium is shaping the future of collaborative drug discovery. Our proven teams of drug discovery professionals are passionate about unlocking the therapeutic potential of both genetically- and clinically-validated drug targets, as well as developing new therapeutic modalities. We work in partnership with our clients to address the most difficult scientific and business challenges facing drug discovery, and to ultimately enable transformational health care outcomes. www.be4.com

@2016 Beryllium Discovery Corp – 844-BE4-FOUR | info@be4.com

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