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SIMPLIFIED HELICAL PROTEINS THAT BIND SPECIFIC DNA SITES

Award Number: R01GM069041
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 09/12/2003
PERIOD OF PERFORMANCE END DATE: 08/31/2007

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SIMPLIFIED HELICAL PROTEINS THAT BIND SPECIFIC DNA SITES - DESCRIPTION (provided by applicant): Libraries of alpha-helical peptides may prove to be useful sources of DNA-binding ligands and provide insight into the requirements for selective DNA recognition. Knowledge of protein structure-function relationships and their impact on protein-DNA interactions can be augmented by concentrating on the basic region/leucine zipper (bZIP) motif, in which a pair of short, basic alpha-helices recognizes the DNA major groove with sequence-specificity and high affinity. This proposal targets the aryl hydrocarbon receptor/nuclear translocator heterodimeric system, suspected of mediating the deleterious health effects of environmental pollutants and interfering with endocrine disruptor pathways. Based on sequence homology, the aryl hydrocarbon receptor (AhR) and the aryl hydrocarbon nuclear translocator (Arnt) are believed to be basic region/helix-loop-helix proteins (bHLH), an alpha-helical DNA-binding motif similar to the bZIP. The goal is to explore the universality of the protein alpha-helix as a scaffold for design of sequence-specific DNA-binding proteins by reducing Nature's constructs to a minimal, ~60 amino-acid helix that serves as an ideal a molecular recognition scaffold (structure). Quantitative examination of how these proteins recognize specific DNA sequences will contribute to our understanding of the determinants of binding specificity in protein-DNA interactions (function). Designed proteins are bacterially expressed and extensively purified. Structure is characterized by circular dichroism; DNA-binding function is characterized by DNase I footprinting. Thermodynamics of cocomplexation is dissected by fluorescence anisotropy and calorimetry, and structural information is obtained by X-ray crystallography and molecular modeling.


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: 2006 ( Subtotal = $158,193 )
2006	2006	UNIVERSITY OF TORONTO	**	TORONTO, ONTARIO		00000		CAN	Biomedical Research and Research Training	000	4	9/14/2006	NON-COMPETING CONTINUATION	$158,193
														Subtotal = $158,193

Issue Date FY: 2005 ( Subtotal = $162,000 )
2005	2005	UNIVERSITY OF TORONTO	**	TORONTO, ONTARIO		00000		CAN	Biomedical Research and Research Training	000	3	9/1/2005	NON-COMPETING CONTINUATION	$162,000
														Subtotal = $162,000

Issue Date FY: 2004 ( Subtotal = $162,000 )
2004	2004	UNIVERSITY OF TORONTO	**	TORONTO, ONTARIO		00000		CAN	Biomedical Research and Research Training	000	2	8/30/2004	NON-COMPETING CONTINUATION	$162,000
														Subtotal = $162,000

Issue Date FY: 2003 ( Subtotal = $162,000 )
2003	2003	UNIVERSITY OF TORONTO	**	TORONTO, ONTARIO		00000		CAN	Cell Biology and Biophysics Research	000	1	9/11/2003	NEW	$162,000
														Subtotal = $162,000

Grand Total All Awards = $644,193

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SIMPLIFIED HELICAL PROTEINS THAT BIND SPECIFIC DNA SITES

Award Number: R01GM069041

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 09/12/2003

PERIOD OF PERFORMANCE END DATE: 08/31/2007

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