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CRYSTALLOGRAPHIC STUDIES ON RIBOSOMAL PARTICLES

Award Number: R01GM034360
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/1985
PERIOD OF PERFORMANCE END DATE: 07/31/2011

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CRYSTALLOGRAPHIC STUDIES ON RIBOSOMAL PARTICLES - DESCRIPTION (provided by applicant): The long-term goal of our project has been and is shedding light on the molecular mechanisms involved in protein biosynthesis. Ribosomes, the universal cell organelles facilitating the translation of the genetic code into proteins, are nucleoprotein assemblies (2.3 mDa approximately 4500 RNA nucleotides and approximately 55 proteins) built of two subunits of unequal size, which associate upon the initiation of protein biosynthesis. The immediate objectives of this proposal are: (a) elucidating the detailed mechanisms involved in peptide bond formation, amino acid polymerization, peptide bond formation, translocation, tRNA release, nascent protein progression, elongation arrest and initial steps towards folding. For these studies carefully designed complexes capturing ribosomal particles at defined functional states, are being prepared, based on the high- resolution structures of the two eubacterial ribosomal subunits determined by us. Examples are complexes of substrate analogs, functional ligands, inhibitors, and non-ribosomal compounds relevant to protein biosynthesis, such as native and mutated trigger factor; (b) Determining the parameters acquiring the effectiveness of ribosomal antibiotics, by careful analysis of the distinction between mere binding and inhibitory action, based on antibiotics binding modes to ribosomes of authentic pathogens, of eubacteria serving as pathogen models, and of archaea resembling eukaryotes; (c) Further advance towards understanding mechanisms attaining resistance to ribosomal antibiotics, by elucidating the structural bases of resistance mechanisms developed against traditional as well as advanced ribosomal antibiotics. Methods: High resolution X-ray diffraction data are being collected at cryogenic temperatures from flash- frozen crystals of complexes of functionally active ribosomes, using high brilliance synchrotron radiation. Phases are being determined by a MIRAS, molecular replacement and crystal averaging. The resulting electron density maps are being interpreted interactively and the positions and orientations of the ligands and/or antibiotics are being compared to available biochemical and mutagenesis data. The significance of ribosomal crystallography stems from its potential to illuminate the mechanism of a fundamental life process, protein biosynthesis, as well as to reveal modes of action of antibiotics targeting ribosomes. These studies have already illuminated principles of drug selectivity, and provided significant basic knowledge of possible pathways of drug resistance, hence paving the way to improve therapeutic properties.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2010 ( Subtotal = $162,000 )
2010	2010	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Biomedical Research and Research Training	000	22	9/13/2010	SUPPLEMENT FOR EXPANSION	$162,000
2010	2009	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Biomedical Research and Research Training	001	22	9/13/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $162,000

Issue Date FY: 2009 ( Subtotal = $256,927 )
2009	2009	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Biomedical Research and Research Training	000	22	7/30/2009	NON-COMPETING CONTINUATION	$256,927
														Subtotal = $256,927

Issue Date FY: 2008 ( Subtotal = $256,927 )
2008	2008	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Biomedical Research and Research Training	000	21	8/11/2008	NON-COMPETING CONTINUATION	$256,927
														Subtotal = $256,927

Issue Date FY: 2007 ( Subtotal = $256,927 )
2007	2007	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Biomedical Research and Research Training	000	20	7/16/2007	NON-COMPETING CONTINUATION	$256,927
														Subtotal = $256,927

Issue Date FY: 2006 ( Subtotal = $264,600 )
2006	2006	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Biomedical Research and Research Training	000	19	8/10/2006	COMPETING CONTINUATION	$264,600
														Subtotal = $264,600

Issue Date FY: 2005 ( Subtotal = $216,000 )
2005	2005	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Biomedical Research and Research Training	000	18	5/26/2005	NON-COMPETING CONTINUATION	$216,000
														Subtotal = $216,000

Issue Date FY: 2004 ( Subtotal = $216,000 )
2004	2004	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Biomedical Research and Research Training	000	17	5/24/2004	NON-COMPETING CONTINUATION	$216,000
														Subtotal = $216,000

Issue Date FY: 2003 ( Subtotal = $216,000 )
2003	2003	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cell Biology and Biophysics Research	000	16	5/26/2003	COMPETING CONTINUATION	$216,000
														Subtotal = $216,000

Issue Date FY: 2001 ( Subtotal = $179,882 )
2001	2001	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cell Biology and Biophysics Research	000	15	5/14/2001	NON-COMPETING CONTINUATION	$179,882
														Subtotal = $179,882

Issue Date FY: 2000 ( Subtotal = $175,370 )
2000	2000	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		76100		ISR	Cell Biology and Biophysics Research	000	14	8/14/2000	NON-COMPETING CONTINUATION	$175,370
														Subtotal = $175,370

Issue Date FY: 1999 ( Subtotal = $170,990 )
1999	1999	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		76100		ISR	Cell Biology and Biophysics Research	000	13	5/24/1999	COMPETING CONTINUATION	$170,990
														Subtotal = $170,990

Grand Total All Awards = $2,371,623

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CRYSTALLOGRAPHIC STUDIES ON RIBOSOMAL PARTICLES

Award Number: R01GM034360

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/1985

PERIOD OF PERFORMANCE END DATE: 07/31/2011

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