about_banner
    2011 RESEARCH NEWS home > about hwi > what does hwi do? > research news  
  2010 Research News
Summaries of Recent Publications by HWI Scientists
  

DrakeInhibiting iron acquisition by human pathogens
Bacteria, like nearly all organisms, require iron to live. However, iron is a limiting resource in many environments, including in many biological fluids. Therefore, to establish an infection bacteria produce chemicals called siderophores that are used for iron acquisition. Pseudomonas aeruginosa is a common human pathogen that produces a siderophore called pyoverdine. The Gulick lab has recently identified the specific roles played by two proteins named PvdL and PvdQ that perform steps in pyoverdine synthesis. Additionally, they have developed a strategy to block PvdQ, finding chemicals that bind to this protein to interfere with its activity. They additionally solved the structure of PvdQ bound to these novel inhibitors. Experiments are underway to continue to characterize this pathway and the ability of these, and improved inhibitors, to block pyoverdine production.   [Learn more]

Alex

  
Structure of a selective drug bound to COX-2
The cyclooxygenases (COX-1 and COX-2) are membrane-associated enzymes that generate prostaglandin H2 from arachidonic acid (AA) in the committed step of prostaglandin biogenesis and are the targets for nonsteroidal anti-inflammatory drugs (NSAIDs). NS-398 was the first in a series of selective drugs designed to preferentially inhibit COX-2, with the aim of ameliorating many of the toxic gastrointestinal side effects caused by conventional NSAID inhibition. The Malkowski lab has determined the X-ray crystal structure of murine COX-2 in complex with NS-398 utilizing synchrotron radiation to 3.0A resolution. Their work shows that NS-398 binds in the cyclooxygenase channel in a conformation that is different from that observed for other COX-2-selective inhibitors.  [Learn more]
Luft

Interpreting the results of crystal growth screening experiments
When a protein sample is sent to Hauptman-Woodward’s high-throughput crystallization screening laboratory to find appropriate chemical conditions for growing crystals suitable for crystal structure determination, 1536 different experiments are set up and observed over several weeks.  This leads to several thousand images that must be examined and interpreted to classify the results of the crystallization experiments.  HWI scientists Eddie Snell and Joe Luft show how a combination of incomplete factorial sampling of crystallization cocktails, standard outcome classification, and visualization of how the outcomes relate chemically can lead to the logical design of subsequent crystallization experiments.  [Learn more]
Grant

Small angle X-ray scattering complements other structure determination tools
Although structural crystallography and nuclear magnetic resonance (NMR) spectroscopy are powerful techniques, they leave many soluble, purified protein samples structurally uncharacterized. Small angle X-ray scattering (SAXS) is a solution technique that provides data on the size and multiple conformations of a sample, and can be used to reconstruct a low-resolution molecular envelope of a macromolecule. The Snell lab has used SAXS in a high-throughput manner on a subset of 28 proteins, where structural information is available from previous crystallographic and/or NMR experiments. These crystallographic and NMR structures were used to validate the accuracy of molecular envelopes reconstructed from SAXS data, to compare and highlight the complementary structural information that SAXS provides, and to leverage biological information derived by crystallographers and spectroscopists from their structures. It was found that the SAXS data agree well with the available structural information. Thus, SAXS is a powerful, albeit low-resolution, technique that can provide additional, complementary structural information to improve the functional interpretation of high-resolution structures.  [Learn more]
Cody
Towards the design of more potent anti-pneumonia drugs
Pneumonia caused by a yeast-like fungus, Pneumocystis jirovecii (pj), is a frequent opportunistic infection in cancer or HIV/AIDS patients or in other people with compromised immune systems. The drug trimethoprim, which targets the fungal version of the essential enzyme dihydrofolate reductase (DHFR), is used for treatment. To aid the development of more potent drugs, The Cody lab examined the crystal structures of mutant forms of pjDHFR.  Their unexpected results show evidence for binding of two trimethoprim molecules to one molecule of the DHFR enzyme.  [Learn more]
back to top
700 Ellicott Street Buffalo, New York 14203-1102 Tel: 716 898 8600 Fax: 716 898 8660