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In situ atomic structures of the Kaposi's sarcoma-associated herpesvirus portal-terminase complex and glycoproteins

Award Number: R01DE025567
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Kaposi's sarcoma (KS) is the most common malignancy associated with infection by human immunodeficiency virus (HIV). As a cancer of endothelial origin that typically grows under the skin or mucous membranes, KS in AIDS patients mostly manifests as oral lesions. Kaposi's sarcoma-associated herpesvirus (KSHV), a member of the gammaherpesvirus subfamily of the Herpesviridae family, has been shown to be an etiologic agent of all forms of KS, primary effusion lymphoma, and multicentric Castleman's disease. Currently, no drugs specifically targeting lytic replication of KSHV are available. Additionally, atomic structures of KSHV viral genome packaging/ejection machinery and fusion-mediating glycoproteins needed for rational design of antiviral drugs and vaccines are unavailable. The prior four-years' funding of this multiple principal investigator (MPI) R01 project has led to the publication of the atomic structure of the KSHV capsid in Nature. Structure-guided mutagenesis studies have identified amino acid interactions among capsid proteins that are essential to capsid assembly and informed the design of small peptide mimics that inhibited viral maturation. Jointly, the MPIs' groups also published the first atomic model of the KSHV DNA-packaging portal complex and capsid associated tegument complexes in Cell. Preliminary data for this renewal application have established the feasibility of obtaining in situ structures of genome-packaging portal-terminase complex and the cell-entry glycoprotein B (gB) in both pre-fusion and post-fusion conformations. These portal protein and envelope glycoprotein structures and structure-guided mutagenesis results have led to three hypotheses: (1) the portal- associated proteins and terminase interactions are vital to KSHV genome encapsidation; (2) the interactions and conformational changes among envelope glycoproteins are required for KSHV fusion with host cells during cell entry; and (3) such interactions revealed in atomic structures can help design inhibitors and vaccines against KSHV lytic infection. The studies described in this application will test the above hypotheses by taking advantage of technology breakthroughs in high-resolution cryoEM and KSHV mutagenesis already demonstrated in the two MPIs' labs in the current funding cycle. In Aim 1, we will determine the in situ structures of KSHV portal-associated proteins and the terminase to ~3Å by cryoEM. From these structures, we will derive atomic models and identify amino- acid residues within 6 Å of interacting proteins (i.e., residues vital to DNA packaging and ejection). In Aim 2, we will determine the structures of major envelope glycoproteins to ~3Å. Specifically, we will characterize the pre- fusion and post-fusion states of gB and the interactions of gH/gL, gM/gN, and K8.1A with their binding partners. In Aim 3, we will refine our structural interpretation through structure-guided mutagenesis and identify target sites for inhibition of genome encapsidation and membrane fusion. Results from this research program will inform future development of drugs and novel vaccines against KSHV infection and spread. The novel approach established will be generally applicable to other viruses and complexes.


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: 2023 ( Subtotal = $416,812 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	9	8/15/2023	NON-COMPETING CONTINUATION	$416,812
														Subtotal = $416,812

Issue Date FY: 2022 ( Subtotal = $416,981 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	004	8	8/24/2022	NON-COMPETING CONTINUATION	$417,047
2022	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	5	6/29/2022	NON-COMPETING CONTINUATION	-$66
2022	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	4	6/29/2022	NON-COMPETING CONTINUATION	$0
2022	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	3	6/29/2022	NON-COMPETING CONTINUATION	$0
2022	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	003	2	6/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $416,981

Issue Date FY: 2021 ( Subtotal = $425,704 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	003	7	8/16/2021	NON-COMPETING CONTINUATION	$425,704
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	5	5/21/2021	NON-COMPETING CONTINUATION	-$103,825
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	6	5/21/2021	COMPETING CONTINUATION	$103,825
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	6	10/13/2020	COMPETING CONTINUATION	$0
														Subtotal = $425,704

Issue Date FY: 2020 ( Subtotal = $813,668 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	005	6	9/23/2020	COMPETING CONTINUATION	$17,499
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	002	5	9/1/2020	NON-COMPETING CONTINUATION	$0
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	004	5	9/23/2020	NON-COMPETING CONTINUATION	-$17,499
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	003	6	9/8/2020	COMPETING CONTINUATION	$428,668
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	5	2/18/2020	NON-COMPETING CONTINUATION	$38,500
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	5	11/21/2019	NON-COMPETING CONTINUATION	$346,500
														Subtotal = $813,668

Issue Date FY: 2019 ( Subtotal = $385,000 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	4	11/20/2018	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2018 ( Subtotal = $385,000 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	3	12/12/2017	NON-COMPETING CONTINUATION	$346,500
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	3	4/24/2018	NON-COMPETING CONTINUATION	$38,500
														Subtotal = $385,000

Issue Date FY: 2017 ( Subtotal = $385,000 )
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	11000 KINROSS AVE STE 102	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	2	11/18/2016	NON-COMPETING CONTINUATION	$346,500
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	2	5/23/2017	NON-COMPETING CONTINUATION	$38,500
														Subtotal = $385,000

Issue Date FY: 2016 ( Subtotal = $385,000 )
2016	2016	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	1	11/20/2015	NEW	$385,000
														Subtotal = $385,000

Grand Total All Awards = $3,613,165

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In situ atomic structures of the Kaposi's sarcoma-associated herpesvirus portal-terminase complex and glycoproteins

Award Number: R01DE025567

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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