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  • Vanderbilt Institute of Chemical Biology
    that block the function of a protein that transports potassium ions across cell membranes Their anti seizure activity in mice suggests a possible new approach for the treatment of epilepsy Jerod Denton and David Weaver the creation of a molecule that can be used with PET positron emission tomography imaging to detect cells undergoing a form of cell death This imaging agent may be used to monitor the response of cancer to therapy Charles Manning the discovery of molecules that activate proteins involved in olfaction the sense of smell in mosquitoes These molecules may serve as a very effective mosquito repellant that could both fend off an irritating pest and be used to control malaria a devastating disease in the developing world Larry Zwiebel the identification of new molecules that are toxic to bacteria growing under low oxygen conditions These compounds are being investigated as potential new drugs to treat antibiotic resistant bacterial infections Eric Skaar and Gary Sulikowski the development of new highly innovative diagnostic tests for malaria Their devices which can be used easily in the field allows asymptomatic carriers to be identified and treated so they do not serve as a source for further spread of the malaria parasite David Wright and Rick Haselton VICB researchers such as these have been highly successful in obtaining funding for their research However maintaining the environment that supports their work also requires money that cannot easily be obtained through typical grant applications Your support will help to keep the VICB strong so that these and other vital research programs will continue to thrive Contact Development and Alumni Relations Vanderbilt University Medical Center Development and Alumni Relations 2525 West End Ave Suite 450 Nashville TN 37203 medicalgiving vanderbilt edu Local 615 936 0230 Free 800 288 0028 Fax 615 936 7425

    Original URL path: http://www.vanderbilt.edu/vicb/donate.html (2016-02-16)
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  • Vanderbilt Institute of Chemical Biology - New Approach to Cancer Therapy Targets the Hedgehog Signaling Pathway
    focused on replication of the telomeric DNA found at the terminus of all chromosomes In vertebrates telomeres comprise long up to 15 kb stretches of repeated 5 TTAGGG 3 3 AATCCC 5 sequences Figure 2 The repetitive sequence allows the DNA to form physiological t loop structures but it also enables the formation of aberrant structures that can lead to replication stress The potential damage this can cause is exacerbated by the fact that telomeric DNA contains few origins of replication so if a replication fork becomes stalled there are limited opportunities to restart the process Figure 2 Structure of the vertebrate telomere a The telomere comprises 5 TTAGGG 3 3 AATCCC 5 repeats of 4 to 14 kb in length in normal human cells The end of the 5 TTAGGG 3 strand is extended for 130 230 nucleotides as a single stranded tail b The telomere may form a t loop structure with the single stranded tail displacing a region of the duplex to pair with its complementary 3 AATCCC 5 strand c d Both the linear and looped structures are stabilized and protected by a coating of shelterin complex proteins The shelterin complex includes TRF1 and TRF2 which bind directly to the DNA duplex POT1 which binds to the single stranded tail and TPP1 TIN2 and RAP1 which interact with the DNA indirectly by binding to the other proteins Figure reproduced by permission from Macmillan Publishers Ltd from A J Cesare R R Reddel 2001 Nat Rev Gen 11 319 Copyright 2010 To determine if SMARCAL1 plays a role in ensuring efficient replication of telomeric DNA the Cortez lab investigators used siRNA to knockdown expression of the protein in HeLa1 3 cells followed by fluorescence microscopy to search for evidence of DNA damage at telomeres during S phase of the cell cycle Their results Figure 3 showed that indeed SMARCAL1 knockdown led to an accumulation of the DNA damage response proteins 53BP1 and RPA at sites enriched with the 5 TTAGGG 3 sequence They designated these sites telomere dysfunction induced foci TIFs The increase in TIFs was abrogated when the researchers transfected SMARCAL1 siRNA treated cells with an siRNA resistant gene encoding wild type SMARCAL1 Rather unexpectedly transfection with a gene encoding an N terminal deletion mutant of SMARCAL also reduced the TIF increase observed in SMARCAL1 siRNA treated cells These findings suggested that SMARCAL1 is required for normal replication of telomeric DNA However they also indicated that SMARCAL1 does not need to interact with RPA to execute this function as the N terminal deletion mutant lacked the RPA binding domain Figure 3 SMARCAL1 is required for successful telomere replication HeLa1 3 cells were transfected with siRNA directed against SMARCAL1 siSM1 1 or with nontargeting siRNA siNT The cells were then stained with DAPI to label the nuclei a fluorescent antibody against 53BP1 a DNA damage response protein and a fluorescent telomeric DNA probe TTAGGG Fluorescence microscopy revealed that knockdown of SMARCAL1 led to an increase in 53BP1

    Original URL path: http://www.vanderbilt.edu/vicb/discovery_featured1.html (2016-02-16)
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  • Vanderbilt Institute of Chemical Biology_New Role for Inositol Phosphates Discovered
    flies it was possible to obtain ipk2 homozygous mutant larvae completely lacking the enzyme from conception The investigators discovered that like the previously studied ipk2 homozygous mutants the GLC larvae developed however upon pupation they were distinguished by the total absence of an epidermis and its accompanying structures such as developing legs wings or antennae Figure 2 Figure 2 Comparison of wild type A conventional zygotic ipk2 homozygous mutant B and ipk2 germ line clone mutant pupae Figure reproduced by permission from A M Seeds 2015 Proc Natl Acad Sci U S A published online Dec 8 DOI 10 1073 pnas 1514684112 Copyright 2015 A M Seeds et al The defects observed in the GLC pupae suggested that Ipk2 is required for proper development of imaginal discs clusters of cells that develop into external adult structures during pupation The investigators found that disc precursor structures formed normally in GLC larvae so they hypothesized that either excessive cell death inadequate cell proliferation or both could account for the failure of the imaginal discs to develop in the absence of Ipk2 Apoptosis the process of programmed cell death plays an important role in tissue remodeling during development however excess apoptosis can lead to abnormalities The York lab researchers discovered a higher number of apoptotic cells in imaginal discs but not in other tissues of ipk2 homozygous mutant pupae As in other organisms apoptosis in the fruit fly is mediated through the action of specialized proteases known as caspases The major initiating caspase in Drosophila is Dronc Selective expression of p35 a protein caspase inhibitor in the wing imaginal discs of developing ipk2 flies reduced the number of dying cells in these structures Consistently ipk2 mutants that also carried a double null mutation for dronc failed to exhibit increased imaginal disc cell death confirming that the excessive death observed in the mutants was due to apoptosis Further studies revealed that loss of the proapoptotic p53 protein did not rescue the ipk2 mutants imaginal disc apoptosis and although the proapoptotic JNK signaling pathway was clearly activated in the ipk2 mutants it was also not required to initiate the observed increase in apoptosis in the imaginal discs Although the investigators had demonstrated increased apoptosis in the ipk2 imaginal discs they quickly learned that this did not fully explain the developmental failure of these structures Indeed 5 bromo 2 deoxyuridine incorporation and clonal analysis studies revealed lower levels of cell proliferation in the imaginal discs of ipk2 mutants as compared to those of wild type flies Previous work had shown that Ipk2 is a regulator of the JAK STAT Janus kinase signal transducers and activators of transcription pathway Figure 3 which plays an important role in the regulation of cell proliferation differentiation and survival In Drosophila the pathway comprises the extracellular ligand Unpaired Upd which binds to its transmembrane receptor Domeless Dome This activates Hopscotch Hop a Dome associated Janus tyrosine kinase which then phosphorylates both itself and Dome The resulting phosphotyrosines provide docking sites for

    Original URL path: http://www.vanderbilt.edu/vicb/discovery_featured2.html (2016-02-16)
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  • Vanderbilt Institute of Chemical Biology - Restoring Homeostasis in the Face of Overnutrition
    sites in the protein For investigation of EmrE dynamics the Mchaourab lab already had a library of DNA constructs of single cysteine mutants available from their prior work Each protein contained a single label in one of the TMs or a loop connecting the TMs Because the subunits adopt an antiparallel orientation the label on each subunit is localized on opposite ends of the dimer providing insight into the movement of each segment of the protein between the two monomers Figure 2 FIGURE 2 Location of representative spin labels in the TM regions used in the study For each spin label pair DEER data measuring the probability distribution P r for the distance r between the labels is shown Distinct distributions between intermediates suggest the existence of multiple conformations Broad distributions especially under pH 8 conditions suggest protein flexibility Sharper peaks indicating a more restricted set of conformations are seen upon the switch to pH 5 or particularly addition of TPP Image reproduced by permission from R Dastvan et al 2016 Proc Natl Acad Sci U S A published online January 19 DOI 10 1073 pnas 1520431113 Copyright 2016 R Dastvan et al To attempt to capture the full range of protein conformations the investigators generated DEER data under three sets of conditions They used pH 5 to mimic the acidic environment of the bacterial periplasmic space conditions that were expected to result in protonation of EmrE Conversely they chose pH 8 to mimic cytoplasmic conditions that were expected to generate an unbound apo form of the protein Addition of TPP at pH 8 yielded a substrate bound conformation Because proteins are not rigid static structures DEER data are actually distributions that provide the probability that the two labels will be at a particular distance from each other in a given state A broad distribution suggests conformational flexibility between the two labeled sites while a narrow distribution suggests rigidity As expected the DEER data confirmed that the protein adopted distinct conformations under each of the three experimental conditions Data for the TPP bound conformation agreed with their prior work indicating discrepancies with the crystal structure Furthermore the data ruled out the hypothesis that a simple alternation of the subunits between two different conformations could explain EmrE dependent transport As the researchers noted if the protein simply fluctuated between two identical structures that differed only in membrane orientation DEER would not distinguish conformational changes between those structures According to the DEER results the unbound apo state of EmrE is highly dynamic This flexibility likely plays a role in the protein s ability to bind substrates with a wide range of structures Binding of either a proton or TPP results in a reduction in protein flexibility which is seen most dramatically for TPP binding Figure 2 Switching from the TPP bound to the protonated state results in major structural changes particularly in TM1 TM2 and TM3 and in the loops joining these TMs Figure 3 Although the investigators carried out most of

    Original URL path: http://www.vanderbilt.edu/vicb/discovery_featured3.html (2016-02-16)
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  • Vanderbilt Insitute of Chemical Biology - Fighting Drug Resistance in Tuberculosis
    common mutations found in fluoroquinolone resistant M tuberculosis isolated in the clinic Figure 2 Structures of fluoroquinolones and fluoroquinolone derivatives used in the study The C3 C4 ketoacid functionality that binds the metal ion in the water metal ion bridge is highlighted in red The C8 substituent that was found to influence activity against M tuberculosis DNA gyrase is highlighted in blue FIGURE 3 Close up view of the water metal ion bridge formed between moxifloxacillin and topoisomerase IV from A Baumannii DNA is in green enzyme residues are in gray moxifloxacillin is in yellow the Mg 2 ion is a light green sphere and the water molecules are shown as red spheres Image reproduced by permission from Macmillan Publishers Ltd from A Wohlkonig et al 2010 Nat Struct Mol Biol 17 1152 Copyright 2010 All four of the mutant enzymes exhibited DNA supercoiling and cleavage activity comparable to that of the wild type enzyme However the A90V D94G and D94H mutants were resistant to the effects of two prototypical fluoroquinolones ciprofloxacin cipro and moxifloxacin moxi as determined by their ability to induce increased DNA cleavage by the enzymes The aspartate 94 mutants were more resistant to the effects of both drugs than were the serine 90 mutant and all of the mutants were more resistant to cipro than to moxi In contrast the A90S mutant was more sensitive to the effects of the fluoroquinolones than the wild type enzyme These results suggest that both alanine 90 and aspartate 94 play some role in the interaction of fluoroquinolones with M tuberculosis gyrase possibly through the formation of a water metal ion bridge Quinazolinediones containing a 3 aminomethyl pyrrolidinyl 3 AM P substituent at C7 Figure 4 are effective topoisomerase II poisons through interaction between the 3 AM P substituent and the enzyme rather than formation of a water metal ion bridge Consistently the ability of 8 methyl 3 AM P dione to induce DNA break formation by M tuberculosis gyrase was unaffected by the three mutants predicted to disrupt water metal ion bridge formation This was also true for 8 methyl 3 AM P FQ a fluoroquinolone bearing the 3 AM P substituent at C7 However the A90S mutant was more sensitive to 8 methyl 3 AM P FQ than the wild type gyrase whereas this was not observed in the case of 8 methyl 3 AM P dione As prior work had suggested an important role for a C8 substituent in the activity of fluoroquinolones the investigators assessed the potency of 8 H 3 AM P dione and 8 H 3 AM P FQ compounds lacking a substituent at C8 As expected removal of the C8 methyl group resulted in a loss of activity against all enzymes tested Together these results suggest that a water metal ion bridge formed predominantly through aspartate 94 plays a role in fluoroquinolone binding to M tuberculosis gyrase but that substituents at C7 and C8 are also important to drug potency FIGURE 4 Structures

    Original URL path: http://www.vanderbilt.edu/vicb/discovery_featured4.html (2016-02-16)
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  • VICB CBI Program Overview
    training program Significant biological training is provided to students receiving in depth training in synthetic mechanistic chemistry and significant training in synthetic mechanistic chemistry is provided to students receiving in depth training in the biological sciences Highlights of the training program include a chemical biology curriculum elective courses for specialized training an interactive seminar series in chemical biology an annual research retreat and an in depth laboratory research experience including lab rotations Students are well grounded in a core discipline and sufficiently well trained in complementary fields to allow them to work effectively in a multi disciplinary environment Trainees obtain Ph D degrees working with research advisors in the Departments of Biochemistry Chemistry Microbiology and Immunology Molecular Physiology and Biophysics and Pharmacology Commitment to diversity Vanderbilt is committed to the principles of equal opportunity and affirmative action Vanderbilt provides reasonable accommodations for students with disabilities The Equal Opportunity Affirmative Action and Disability Services department is responsible for coordinating disability support services and monitoring the accessibility of programs activities and buildings for the Vanderbilt University and Medical Center communities consistent with the Americans with Disabilities Act of 1990 and Section 504 of the Rehabilitation Act of 1973 The DSP staff assists departments with providing reasonable accommodations for students faculty and staff with disabilities ensures that Vanderbilt programs and events are accessible to the Vanderbilt community and visitors monitors the accessibility of the university and medical center buildings investigates disability discrimination complaints and provides training on disability related issues Students needing disability related assistance can contact the EAD at http www vanderbilt edu ead For Student Services http www vanderbilt edu ead ds students html For Faculty Services http www vanderbilt edu ead ds emp html Training http www vanderbilt edu ead train html Campus Location Baker Building Suite 108 GPS Address

    Original URL path: http://www.vanderbilt.edu/vicb/CBI/cbi_program_overview.html (2016-02-16)
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  • Vanderbilt Institute of Chemical Biology
    Closer Look at DNA Replication with iPOND July 14 2011 AlkD s Novel Approach to DNA Repair October 29 2010 Prime Time for DNA Replication August 27 2010 Biochemistry Bioengineering Constructing a Biosynthetic Pathway in Reverse March 28 2014 Harnessing the Circadian Clock to Boost Useful Bioproduction in Cyanobacteria November 20 2013 Lipids Biochemical Collaboration Leads to Novel Biologically Active Lipids April 25 2011 Are Your Lipids Stressed Out January 25 2010 Mechanisms of Cytotoxicity Functional Impact of Protein Modification by Lipid Electrophiles January 30 2014 Signaling New Role for Inositol Phosphates Discovered December 15 2015 Restoring Homeostasis in the Face of Overnutrition October 23 2015 Exploring the Dynamics of Active Transport October 10 2014 A Global View of S Sulfenylation September 9 2014 Energetics of the Activated Receptor G Protein Interaction December 13 2013 Probing Arrestin Conformation November 5 2012 New Insights into G Protein Receptor Coupling June 10 2011 Proteins Structure Function The Complex Interplay of Substrates with Cyclooxygenase 2 September 22 2015 Exploring the Mechanism of Microtubule Directed Motion July 15 2015 Bromide Ion is Essential for Life June 24 2014 Bringing Order to Chaos April 25 2014 Sulfilimine Cross Links A Key to Tissue Evolution January 2 2014 Key to Collagen Cross Links August 28 2012 Protein Symmetry by Design October 18 2011 Backscattering Interferometry Shining Light on Protein Ligand Interactions March 28 2011 Transcription How MicroRNAs Modulate Gene Expression April 12 2013 Survival Advantage Conveyed by Non Optimal Codon Usage February 26 2013 Novel Chemistry Reversing Polarity to Conserve Chirality June 24 2010 Nature s Approach to Solar Power March 3 2010 Recent News Slight Chemical Change May Improve TB Treatments Study February 11 2016 Dynamics of a Drug Resistance Transporter February 5 2016 Faulty Building Blocks in DNA January 28 2016 Wenbiao Chen Named 2016 Chancellor Faculty Fellow January 21 2016 Crystal Structure Reveals Secrets of Virulent Bacterium January 14 2016 New Method Aids Heart Disease Studies Drug Discovery Efforts See Newsclip January 8 2016 Copying Chromosome Caps January 8 2016 Jens Meiler Receives Humboldt Foundation Award December 15 2015 Vanderbilt Ono Pharmaceutical Sign Drug Discovery Agreement December 10 2015 Fighting Type 2 Diabetes with FGF1 November 19 2015 Study Helps Clarify Components of DNA Copy Machine November 12 2015 Study Further Links Immune Response Serotonin Signaling November 5 2015 Detect and Defend Against Pathogens November 4 2015 Chazin Honored with International Biophysics Award October 23 2015 Lindsley on List of Most Frequently Cited VUMC Researchers October 8 2015 Rational Design of Novel Antifungals October 7 2015 VICC Investigators Land Komen Breast Cancer Grants October 6 2015 The Yin and Yang of COX 2 October 2 2015 Collaboration Seeks to Develop New Therapies for Bone Other Diseases October 1 2015 Former Lindsley Lab Student and Vanderbilt PhD Chemistry 14 Among Inaugural Beckman Postdoctoral Fellows September 17 2015 How to Build a Basement September 9 2015 Hudson Named Earl Sutherland Prize for Achievement in Research Prize Winner August 27 2015 Framework for Studying Cell Responses

    Original URL path: http://www.vanderbilt.edu/vicb/news.html (2016-02-16)
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  • Vanderbilt Institute of Chemical Biology
    approaches in studies of G Protein Coupled Receptors one of the most important classes of sensor molecules in cell signaling and a common therapeutic target In addition to the monetary prize this award will promote the Vanderbilt CSB VICB alliance with colleagues at Leipzig University in Germany and provide opportunities to spend up to one year collaborating at the university on a long term research project Read More Here Vanderbilt

    Original URL path: http://www.vanderbilt.edu/vicb/announcements/meiler_award.html (2016-02-16)
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