UNRAVELLING THE BINDING AND ACTIVATION MECHANISM OF A COMPLEX G PROTEIN-COUPLED RECEPTOR

Grant number: 1100676 | Funding period: 2016 - 2019

Completed

Abstract

The peptide hormone relaxin is currently in a Phase III trial for the treatment of heart failure. However the peptide is not a good drug as it can't be taken orally and is very expensive to produce. We will study the interaction of relaxin with its cell surface receptor and the mechanisms by which the receptor functions. The knowledge gained will aid in the design of smaller, more potent and orally active forms of relaxin for the treatment of heart failure

Related publications (12)

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Synthetic short-chain peptide analogues of H1 relaxin lack affinity for the RXFP1 receptor and relaxin-like bioactivity. Clues to a better understanding of relaxin agonist design

Annunziata D'Ercole, Silvia Nistri, Lorenzo Pacini, Alfonso Carotenuto, Federica Santoro, Anna Maria Papini, Ross AD Bathgate, Daniele Bani, Paolo Rovero

2022-08-11

The peptide hormone relaxin (RLX), also available as clinical-grade recombinant protein (serelaxin), holds great promise as a card..

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A Real-Time, Plate-Based BRET Assay for Detection of cGMP in Primary Cells

Adam L Valkovic, Martina Kocan, Brad Hoare, Sarah Marshall, Daniel J Scott, Ross AD Bathgate

2022-02-01

Cyclic guanosine monophosphate (cGMP) is a second messenger involved in the regulation of numerous physiological processes. The mo..

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Structural Insights into the Unique Modes of Relaxin-Binding and Tethered-Agonist Mediated Activation of RXFP1 and RXFP2

Ashish Sethi, Shoni Bruell, Tim Ryan, Fei Yan, Mohammad Hossein Tanipour, Yee-Foong Mok, Chris Draper-Joyce, Yogesh Khandokar, Riley D Metcalfe, Michael DW Griffin, Daniel J Scott, Mohammad Akhter Hossain, Emma J Petrie, Ross AD Bathgate, Paul R Gooley

2021-09-08

Our poor understanding of the mechanism by which the peptide-hormone H2 relaxin activates its G protein coupled receptor, RXFP1 an..

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Conformational Changes in Tyrosine 11 of Neurotensin Are Required to Activate the Neurotensin Receptor 1

Fabian Bumbak, Trayder Thomas, Billy J Noonan-Williams, Tasneem M Vaid, Fei Yan, Alice R Whitehead, Shoni Bruell, Martina Kocan, Xuan Tan, Margaret A Johnson, Ross AD Bathgate, David K Chalmers, Paul R Gooley, Daniel J Scott

2020-08-14

Cell-cell communication via endogenous peptides and their receptors is vital for controlling all aspects of human physiology and m..

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The anti-fibrotic actions of relaxin are mediated through AT(2)R-associated protein phosphatases via RXFP1-AT(2)R functional crosstalk in human cardiac myofibroblasts

Chao Wang, Anita A Pinar, Robert E Widdop, Mohammed A Hossain, Ross AD Bathgate, Kate M Denton, Barbara K Kemp-Harper, Chrishan S Samuel

2020-04-16

Fibrosis is a hallmark of several cardiovascular diseases. The relaxin family peptide receptor 1 (RXFP1) agonist, relaxin, has rap..

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Familial bilateral cryptorchidism is caused by recessive variants in RXFP2

Katie Ayers, Rakesh Kumar, Gorjana Robevska, Shoni Bruell, Katrina Bell, Muneer A Malik, Ross A Bathgate, Andrew Sinclair

2019-11-01

BACKGROUND: Cryptorchidism or failure of testicular descent is the most common genitourinary birth defect in males. While both the..

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Using the novel HiBiT tag to label cell surface relaxin receptors for BRET proximity analysis

Bradley L Hoare, Martina Kocan, Shoni Bruell, Daniel J Scott, Ross AD Bathgate

2019-08-01

Relaxin family peptide 1 (RXFP1) is the receptor for relaxin a peptide hormone with important therapeutic potential. Like many G p..

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Single chain peptide agonists of relaxin receptors

Praveen Praveen, Martina Kocan, Adam Valkovic, Ross Bathgate, Mohammed Akhter Hossain

2019-05-01

There are seven human relaxin family peptides that have two chains (A and B) and three disulfide bonds. The target receptors for f..

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Multi-Component Mechanism of H2 Relaxin Binding to RXFP1 through NanoBRET Kinetic Analysis

Bradley L Hoare, Shoni Bruell, Ashish Sethi, Paul R Gooley, Michael J Lew, Mohammed A Hossain, Asuka Inoue, Daniel J Scott, Ross AD Bathgate

2019-01-25

The peptide hormone H2 relaxin has demonstrated promise as a therapeutic, but mimetic development has been hindered by the poorly ..

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Real-time examination of cAMP activity at relaxin family peptide receptors using a BRET-based biosensor

Adam L Valkovic, Miranda B Leckey, Alice R Whitehead, Mohammed A Hossain, Asuka Inoue, Martina Kocan, Ross AD Bathgate

2018-10-01

Relaxin family peptide (RXFPs) 1-4 receptors modulate the activity of cyclic adenosine monophosphate (cAMP) to produce a range of ..

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Challenges in the design of insulin and relaxin/insulin-like peptide mimetics

Mohammed Akhter Hossain, Ross AD Bathgate

2018-06-01

Peptidomimetics are designed to overcome the poor pharmacokinetics and pharmacodynamics associated with the native peptide or prot..

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Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin

Shoni Bruell, Ashish Sethi, Nicholas Smith, Daniel J Scott, Mohammed Akhter Hossain, Qing-Ping Wu, Zhan-Yun Guo, Emma J Petrie, Paul R Gooley, Ross AD Bathgate

2017-06-12

Relaxin family peptide receptor 2 (RXFP2) is a GPCR known for its role in reproductive function. It is structurally related to the..