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STRUCTURE-FUNCTION AND INHIBITION OF RNR1

Award Number: R01CA100827
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/12/2003
PERIOD OF PERFORMANCE END DATE: 07/31/2012

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STRUCTURE-FUNCTION AND INHIBITION OF RNR1 - DESCRIPTION (provided by applicant): Ribonucleotide Reductase, (RNR) is a multi-subunit enzyme that catalyzes the rate-limiting step of de novo precursor DMA synthesis by converting nucleotide diphosphates to deoxynucleotide diphosphates. Crucial for rapidly proliferating cells, RNR is a target for anti-cancer and anti-viral therapy. Recently, we solved the first X -ray structures of eukaryotic ribonucleotide reductase 1 from Saccharomyces cerevisiae. The twelve structures solved reveal two new domains, the structural basis for substrate selection in eukaryotes and the mode of binding of the anti-cancer drug Gemcitabine and ribonucleotide reductase based peptides; the latter complex provides a framework for designing anti-cancer drugs that disrupt the enzyme's multi-subunit assembly. We have expressed and purified the human Rnr1 for crystallization. Until the mammalian Rnr1 structure is solved, the yeast structures provide an invaluable starting point for designing inhibitors that target Rnr1. We will solve the X-ray structures of Rnr1 complexed with inhibitors that target the effector sites (Eg. Clofarabine) and catalytic site (3NUDP) as well as bifunctional molecules that target both effector and catalytic sites (dGTP-ADP linked covalently), and peptidomimetics that disrupt RNR assembly. These structures will provide a starting point for knowledge based drug design. As a proof of principle we have shown that a mouse Rnr2 based inhibitor binds yeast Rnr1. The compounds have been provided by our collaborators Dr. Barry Cooperman (UPENN), Dr. Vasha Ghandi (MD Anderson), and Dr. Willam Parker at the Southern Research Institute. We will also study how SmM binds Rnr1 using cross-linking, limited proteolysis, surface mapping in tandem with mass spectrometry. The structures of intact Sml1-Rnr1 and Rnr1-Sml1peptide complexes will be determined. We will use site-directed mutagenesis to confirm the MS results on the Sml1 binding site, identify the function of the newly identified insert domains and the role of crucial residues identified by our structures that confer substrate specificity. Finally, we will investigate the structural basis of the synthetically lethal mismatch repair mutants identified by Dr. Julian Simon at the Fred Hutchninson Cancer Center. The work proposed will further our understanding on how the vital enzyme ribonucleotide reductase is regulated and the structure based design of inhibitors against it will be important for the therapeutic intervention of proliferative diseases such as cancer.


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: 2011 ( Subtotal = $258,247 )
2011	2011	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	9	7/14/2011	NON-COMPETING CONTINUATION	$258,247
														Subtotal = $258,247

Issue Date FY: 2010 ( Subtotal = $278,640 )
2010	2010	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	8	7/15/2010	NON-COMPETING CONTINUATION	$278,640
														Subtotal = $278,640

Issue Date FY: 2009 ( Subtotal = $683,472 )
2009	2009	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	7	7/9/2009	NON-COMPETING CONTINUATION	$278,882
2009	2009	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Trans-NIH Recovery Act Research Support	001	7	9/1/2009	SUPPLEMENT FOR EXPANSION	$404,590
														Subtotal = $683,472

Issue Date FY: 2008 ( Subtotal = $278,782 )
2008	2008	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	6	7/31/2008	NON-COMPETING CONTINUATION	$278,782
														Subtotal = $278,782

Issue Date FY: 2007 ( Subtotal = $260,934 )
2007	2007	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cancer Biology Research	000	4	8/13/2007	COMPETING CONTINUATION	$260,934
														Subtotal = $260,934

Issue Date FY: 2006 ( Subtotal = $44,674 )
2006	2006	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cancer Biology Research	001	3	8/21/2006	SUPPLEMENT FOR EXPANSION	$44,674
														Subtotal = $44,674

Issue Date FY: 2005 ( Subtotal = $241,063 )
2005	2005	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cancer Biology Research	000	3	6/6/2005	NON-COMPETING CONTINUATION	$241,063
														Subtotal = $241,063

Issue Date FY: 2004 ( Subtotal = $241,063 )
2004	2004	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cancer Biology Research	000	2	5/7/2004	NON-COMPETING CONTINUATION	$241,063
														Subtotal = $241,063

Issue Date FY: 2003 ( Subtotal = $241,063 )
2003	2003	UNIVERSITY OF TENNESSEE	WEST CUMBERLAND AVENUE, SW	KNOXVILLE	TN	37916	KNOX	USA	Cancer Biology Research	000	1	6/12/2003	NEW	$241,063
														Subtotal = $241,063

Grand Total All Awards = $2,527,938

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STRUCTURE-FUNCTION AND INHIBITION OF RNR1

Award Number: R01CA100827

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/12/2003

PERIOD OF PERFORMANCE END DATE: 07/31/2012

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