This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mechanism of inhibition of secreted phospholipase A2 Secreted phospholipase A2 (sPLA2) enzymes regulate cytokine-mediated inflammatory pathways. Exogenous Group IIA sPLA2 (sPLA2-IIA) can enhance tumour necrosis factor (TNF)-stimulated prostaglandin E2 (PGE2) production via the upregulation of NF-B-dependent cyclooxygenase(COX) protein levels in fibroblast-like synovial cells from RA patients1. The activity of cytoplasmic PLA2-(cPLA2-) is required. Proliferation of prostate cancer cells induced by exogenous sPLA2-IIA requires both sPLA2-IIA enzyme activity and cPLA2- activity2. Thus, exogenous sPLA2-IIA modulates cell function by distinct context-dependent mechanisms. We have developed inhibitors that block both the enzymatic and activity independent actions of sPLA2-IIA3 requiring the elucidation of the structure of sPLA2-IIA complexed with our inhibitors. We have grown several different crystal forms of sPLA2-IIA4 in the presence of our inhibitors, a number of which have been solved and refined from several 2.8 Ǻ datasets collected in-house. There is strong evidence of our inhibitors complexed with sPLA2-IIA, however the inhibitor density is not sufficiently well-resolved to determine the precise interactions of our inhibitors from current data. We require high precision, high resolution datasets in order to better define the structure and interactions of the inhibitors and in turn provide valuable insight into the mechanism by which sPLA2-IIA exerts its effects in inflammatory diseases and prostate cancer. 1Bidgood, M.J. et al(2000) J.. Immunol. 165, 2790;2Sved, P. et al(2004) Cancer Res. 64, 6934; 3Church, W.B. et al(2001), J. Biol. Chem. 276, 33156; 4Church, W.B. et al(2000),Acta Cryst. D56,1482
| Weingarten, Adam S; Dannenhoffer, Adam J; Kazantsev, Roman V et al. (2018) Chromophore Dipole Directs Morphology and Photocatalytic Hydrogen Generation. J Am Chem Soc 140:4965-4968 |
| Yang, Cheolhee; Choi, Minseo; Kim, Jong Goo et al. (2018) Protein Structural Dynamics of Wild-Type and Mutant Homodimeric Hemoglobin Studied by Time-Resolved X-Ray Solution Scattering. Int J Mol Sci 19: |
| Kazantsev, Roman V; Dannenhoffer, Adam J; Weingarten, Adam S et al. (2017) Crystal-Phase Transitions and Photocatalysis in Supramolecular Scaffolds. J Am Chem Soc 139:6120-6127 |
| Fournier, Bertrand; Sokolow, Jesse; Coppens, Philip (2016) Analysis of multicrystal pump-probe data sets. II. Scaling of ratio data sets. Acta Crystallogr A Found Adv 72:250-60 |
| Cho, Hyun Sun; Schotte, Friedrich; Dashdorj, Naranbaatar et al. (2016) Picosecond Photobiology: Watching a Signaling Protein Function in Real Time via Time-Resolved Small- and Wide-Angle X-ray Scattering. J Am Chem Soc 138:8815-23 |
| Pande, Kanupriya; Hutchison, Christopher D M; Groenhof, Gerrit et al. (2016) Femtosecond structural dynamics drives the trans/cis isomerization in photoactive yellow protein. Science 352:725-9 |
| Weingarten, Adam S; Kazantsev, Roman V; Palmer, Liam C et al. (2015) Supramolecular Packing Controls H? Photocatalysis in Chromophore Amphiphile Hydrogels. J Am Chem Soc 137:15241-6 |
| Pfoh, Roland; Pai, Emil F; Saridakis, Vivian (2015) Nicotinamide mononucleotide adenylyltransferase displays alternate binding modes for nicotinamide nucleotides. Acta Crystallogr D Biol Crystallogr 71:2032-9 |
| Mariette, Céline; Guérin, Laurent; Rabiller, Philippe et al. (2015) The creation of modulated monoclinic aperiodic composites in n-alkane/urea compounds. Z Kristallogr Cryst Mater 230:5-11 |
| Yang, Xiaojing; Stojkovi?, Emina A; Ozarowski, Wesley B et al. (2015) Light Signaling Mechanism of Two Tandem Bacteriophytochromes. Structure 23:1179-89 |
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