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Structural basis of prothrombin activation

Award Number: R01HL049413
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/1994
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Structural basis of prothrombin activation - Abstract Work under previous support has continued to advance basic knowledge in the field of hemostasis and thrombosis with significant contributions to the structural understanding of thrombin dynamics and prothrombin activation. Unraveling the architecture of coagulation factors and their complexes remains a challenging task because of the difficulty of obtaining high resolution structures for proteins containing multiple domains. We have addressed this challenge by being among the pioneers of using cryo-EM in the field of hemostasis and thrombosis. We have solved the structures of factors V, Va, V short and most notably that of the prothrombin- prothrombinase complex that has documented, for the first time, the initial step of prothrombin activation along the meizothrombin pathway. We will build upon the progress made under previous support and address the structural basis of prothrombin activation, that remains an important unresolved issue in the field. Using cryo- EM, we will dissect the entire kinetic scheme that defines how prothrombinase activates prothrombin along the meizothrombin (cleavage at R320 first) and prethrombin-2 (cleavage at R271 first) pathways. We will characterize the interaction of prothrombinase with prothrombin and meizothrombin (aim 1), and solve the structures of prothrombin, meizothrombin, and fXa in the free form (aim 2). These studies will unravel the nature of conformational changes and underlying mechanism leading to assembly of the various complexes in the kinetic scheme of activation. We will test the hypothesis that cleavage at R320 takes place with prothrombin in the collapsed closed form whilst cleavage at R271 requires meizothrombin or prothrombin to switch to the elongated open form. We also hypothesize that prothrombinase cleaves R320 and R271 in two different conformations. The proposal is supported by solid preliminary cryo-EM data of the prothrombin-prothrombinase complex on nanodiscs, the meizothrombin-prothrombinase complex, as well as of prothrombin, meizothrombin, and fXa in the free form. Success of the project will significantly advance basic knowledge on the most important step of the coagulation response and provide a strategy for the study of other interactions of biological relevance to blood physiopathology.


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: 2025 ( Subtotal = $512,608 )
2025	2025	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	004	29	6/26/2025	NON-COMPETING CONTINUATION	$51,260
2025	2025	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	003	29	4/15/2025	NON-COMPETING CONTINUATION	$461,348
2025	2024	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	28	3/26/2025	COMPETING CONTINUATION	$0
2025	2024	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	002	28	3/28/2025	COMPETING CONTINUATION	$93,194
2025	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	001	27	3/28/2025	NON-COMPETING CONTINUATION	-$93,194
														Subtotal = $512,608

Issue Date FY: 2024 ( Subtotal = $512,608 )
2024	2024	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	001	28	8/9/2024	COMPETING CONTINUATION	$512,608
2024	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	27	8/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $512,608

Issue Date FY: 2023 ( Subtotal = $378,750 )
2023	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	27	5/3/2023	NON-COMPETING CONTINUATION	$378,750
														Subtotal = $378,750

Issue Date FY: 2022 ( Subtotal = $378,991 )
2022	2022	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	26	5/31/2022	NON-COMPETING CONTINUATION	$378,750
2022	2019	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	001	23	9/26/2022	NON-COMPETING CONTINUATION	$241
														Subtotal = $378,991

Issue Date FY: 2021 ( Subtotal = $378,750 )
2021	2021	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	002	25	6/14/2021	NON-COMPETING CONTINUATION	$378,750
2021	2020	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	001	24	2/20/2021	COMPETING CONTINUATION	$4,881
2021	2019	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	23	2/20/2021	NON-COMPETING CONTINUATION	-$4,881
														Subtotal = $378,750

Issue Date FY: 2020 ( Subtotal = $378,750 )
2020	2020	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	001	24	5/28/2020	COMPETING CONTINUATION	$378,750
2020	2019	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	23	5/20/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $378,750

Issue Date FY: 2019 ( Subtotal = $378,750 )
2019	2019	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	23	1/25/2019	NON-COMPETING CONTINUATION	$378,750
														Subtotal = $378,750

Issue Date FY: 2018 ( Subtotal = $378,750 )
2018	2018	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	22	1/25/2018	NON-COMPETING CONTINUATION	$371,175
2018	2018	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	001	22	6/16/2018	NON-COMPETING CONTINUATION	$7,575
														Subtotal = $378,750

Issue Date FY: 2017 ( Subtotal = $378,750 )
2017	2017	SAINT LOUIS UNIVERSITY	ONE NORTH GRAND	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Cardiovascular Diseases Research	000	21	1/9/2017	NON-COMPETING CONTINUATION	$378,750
														Subtotal = $378,750

Issue Date FY: 2016 ( Subtotal = $378,750 )
2016	2016	SAINT LOUIS UNIVERSITY	3500 LINDELL BLVD/FITZG'D HALL	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Cardiovascular Diseases Research	001	20	1/13/2016	COMPETING CONTINUATION	$378,750
2016	2014	SAINT LOUIS UNIVERSITY	3500 LINDELL BLVD/FITZG'D HALL	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	19	1/11/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $378,750

Issue Date FY: 2014 ( Subtotal = $357,761 )
2014	2014	SAINT LOUIS UNIVERSITY	3500 LINDELL BLVD/FITZG'D HALL	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	19	2/21/2014	NON-COMPETING CONTINUATION	$328,556
2014	2014	SAINT LOUIS UNIVERSITY	3500 LINDELL BLVD/FITZG'D HALL	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	001	19	3/3/2014	NON-COMPETING CONTINUATION	$29,205
														Subtotal = $357,761

Issue Date FY: 2013 ( Subtotal = $347,540 )
2013	2013	SAINT LOUIS UNIVERSITY	3500 LINDELL BLVD/FITZG'D HALL	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	18	2/26/2013	NON-COMPETING CONTINUATION	$328,556
2013	2013	SAINT LOUIS UNIVERSITY	3500 LINDELL BLVD/FITZG'D HALL	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	001	18	7/24/2013	NON-COMPETING CONTINUATION	$18,984
														Subtotal = $347,540

Issue Date FY: 2012 ( Subtotal = $365,063 )
2012	2012	SAINT LOUIS UNIVERSITY	3500 LINDELL BLVD/FITZG'D HALL	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	17	2/28/2012	NON-COMPETING CONTINUATION	$365,063
														Subtotal = $365,063

Issue Date FY: 2011 ( Subtotal = $368,750 )
2011	2011	SAINT LOUIS UNIVERSITY	3500 LINDELL BLVD/FITZG'D HALL	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	16	2/17/2011	NON-COMPETING CONTINUATION	$368,750
														Subtotal = $368,750

Issue Date FY: 2010 ( Subtotal = $368,750 )
2010	2010	SAINT LOUIS UNIVERSITY	3500 LINDELL BLVD/FITZG'D HALL	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	001	15	3/16/2010	COMPETING CONTINUATION	$368,750
2010	2008	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	14	3/4/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $368,750

Issue Date FY: 2008 ( Subtotal = $362,679 )
2008	2008	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	14	4/22/2008	NON-COMPETING CONTINUATION	$362,679
														Subtotal = $362,679

Issue Date FY: 2007 ( Subtotal = $362,679 )
2007	2007	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	13	4/19/2007	NON-COMPETING CONTINUATION	$362,679
														Subtotal = $362,679

Issue Date FY: 2006 ( Subtotal = $373,511 )
2006	2006	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	000	12	4/24/2006	NON-COMPETING CONTINUATION	$373,511
														Subtotal = $373,511

Grand Total All Awards = $9,075,779

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Structural basis of prothrombin activation

Award Number: R01HL049413

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/1994

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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