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Structure and function of PTH class B GPCR

Award Number: R01DK116780
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Structure and function of PTH class B GPCR - Summary The objective of this project is to identify small non-peptidic molecule modulators of the parathyroid hormone type 1 receptor (PTHR), a medically important G protein-coupled receptor (GPCR) regulating blood calcium and phosphate homeostasis, and bone remodeling in response to PTH. Detrimental hypercalcemia caused by excess of blood PTH level, or polymorphisms of PTHR resulting in receptor hyperactivity, osteoporosis, and hypocalce- mia caused by defective PTHR signaling, underlie numerous bone and mineral-ion pathologies affecting public health. Previous support via R01DK-116780 has solved the near-atomic structure of PTHR in complex with Gs and made discoveries that led us to formulate the hypothesis that integrated computational, and pharmacological studies, using high-resolution structures of the PTHR and medicinal chemistry methods, may address the chal- lenge of discovering and developing small molecules capable of allosterically modulating PTHR signaling. Aim 1 will use a combination of computational approaches, including molecular dynamics (MD) simula- tions coupled to elastic network model (ENM)-based methods, to predict PTHR sites that are simultaneously druggable and allosteric, and identify small molecules that can potentially serve as allosteric modulators. These compounds will be iteratively refined and validated with feedback from experiments conducted in Aims 2 and 3. Aim 2 will characterize and optimize (via synthesis and/or modifications using advanced medicinal chem- istry methods) the pharmacological profile and cellular impact of these hit compounds by determining the binding, signaling, and trafficking properties of PTHR in the presence of these compounds. Cell studies will test the func- tional actions of compounds with most interesting pharmacological profiles on osteoblast mineralization and expression of 25-hydroxyvitamin D 1-a-hydroxylase, rate limiting enzyme for the biosynthesis of vitamin D). Aim 3 will carry out single particle cryo-EM studies to solve the structure of PTHR in complex with Gq, the G protein that mediates PTH signaling through Ca2+ and PKC signaling pathways. The new structure(s) will permit us to determine the mechanistic basis by which different G proteins –Gq and Gs– reciprocally couple to the PTHR. Structural data will be further used for simulating the collective dynamics of the complex and the mechanism of allosteric communication between the Gq protein and the orthosteric and allosteric ligand-binding pockets. The significance of this research program lies in its first of its kind computational pipeline integrated with multidisciplinary experimental characterization and validation studies, permitting a precise identification of drug- gable allosteric sites in the PTHR to identify novel small molecules with potential therapeutic utility for the treat- ment of bone and mineral ion diseases. Our research may ultimately prove useful to other peptide hormone GPCRs to identify small molecules as future treatments human diseases.


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: 2026 ( Subtotal = $606,024 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	8/31/2026	NON-COMPETING CONTINUATION	$606,024
														Subtotal = $606,024

Issue Date FY: 2025 ( Subtotal = $606,024 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	6/12/2025	NON-COMPETING CONTINUATION	$60,602
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	4/1/2025	NON-COMPETING CONTINUATION	$545,422
2025	2021	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $606,024

Issue Date FY: 2024 ( Subtotal = $612,966 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	5/3/2024	NON-COMPETING CONTINUATION	$38,309
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	4/10/2024	NON-COMPETING CONTINUATION	$574,657
														Subtotal = $612,966

Issue Date FY: 2023 ( Subtotal = $650,986 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/25/2023	COMPETING CONTINUATION	$650,986
														Subtotal = $650,986

Issue Date FY: 2021 ( Subtotal = $429,297 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/19/2021	NON-COMPETING CONTINUATION	$429,297
														Subtotal = $429,297

Issue Date FY: 2020 ( Subtotal = $429,297 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/19/2020	NON-COMPETING CONTINUATION	$429,297
														Subtotal = $429,297

Issue Date FY: 2019 ( Subtotal = $429,297 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/18/2019	NON-COMPETING CONTINUATION	$429,297
														Subtotal = $429,297

Issue Date FY: 2018 ( Subtotal = $428,611 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/27/2018	NEW	$428,611
														Subtotal = $428,611

Grand Total All Awards = $4,192,502

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Structure and function of PTH class B GPCR

Award Number: R01DK116780

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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