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. In the last few years, our research group has been interested in the study of a cytotoxic marine metabolite, bistramide A. This has led to the first reported total synthesis of the molecule.1 Initially experiments demonstrated that bistramide A exhibited potent cytotoxicity (IC50 = 22-45 nM)2 and selectively modulated PKC activity.3 However, research carried out in our lab showed that it has no effect on PKC. We synthesized a biotinylated analog of bistramide A; which was used to affinity purify it's cellular target-actin. Experiments performed in vitro showed that bistramide A effectively inhibited the polymerization of G-actin to F-actin in a dose dependant manner. It also caused the depolymerization of F-actin.4 In order to fully characterize the interaction between bistramide A and actin a thorough mechanistic and crystallographic study needs to be initiated. The structure-activity relationship (SAR), thus established will be utilized to synthesize simple but potent analogs. With the increasing awareness that the actin cytoskeleton is involved in practically all aspects of cell behavior, as well as cancer, it is important to identify new agents, which will serve as research tools to facilitate the study of actin filament organization and dynamics. These new agents may be potentially useful as chemotherapeutic agents. We have crystallized the Bistramide A-actin complex and obtained preliminary x-ray data upto 2A resolution. We shall be optimizing the ligand structure in a manner that the synthesis is more feasable while the biological profile remains largely unchanged. Optimizing the ligand will require further x-ray studies. We require atomic resolution data to fully characterize the interaction at the atomic level.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR007707-15
Application #
7366175
Study Section
Special Emphasis Panel (ZRG1-BBCB (01))
Project Start
2006-08-01
Project End
2007-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
15
Fiscal Year
2006
Total Cost
$14,410
Indirect Cost
Name
University of Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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
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
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
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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