Determining modes of binding and activation of complex G-protein coupled receptor targets
Grant number: 1043750 | Funding period: 2013 - 2015
The peptide hormones 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 and the related peptide INSL3 with their cell surface receptors and the mechanisms by which the receptors function. The knowledge gained will aid in the design of smaller, more potent and orally active forms of relaxin which will be able to be used as drugs for the treatment of heart failure.
Related publications (16)
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
Cell-cell communication via endogenous peptides and their receptors is vital for controlling all aspects of human physiology and m..
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
BACKGROUND: Cryptorchidism or failure of testicular descent is the most common genitourinary birth defect in males. While both the..
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
The peptide hormone H2 relaxin has demonstrated promise as a therapeutic, but mimetic development has been hindered by the poorly ..
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
Relaxin family peptide (RXFPs) 1-4 receptors modulate the activity of cyclic adenosine monophosphate (cAMP) to produce a range of ..
The relaxin receptor as a therapeutic target - perspectives from evolution Cheek for updates and drug targeting
Ross AD Bathgate, Martina Kocan, Daniel J Scott, M Akhter Hossain, Sara V Good, Sergey Yegorov, Jan Bogerd, Paul R Gooley
The peptide relaxin was first identified as an important circulating hormone during pregnancy over 90 years ago. Research over man..
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
Relaxin family peptide receptor 2 (RXFP2) is a GPCR known for its role in reproductive function. It is structurally related to the..
ML290 is a biased allosteric agonist at the relaxin receptor RXFP1
Martina Kocan, Mohsin Sarwar, Sheng Y Ang, Jingbo Xiao, Juan J Marugan, Mohammed A Hossain, Chao Wang, Dana S Hutchinson, Chrishan S Samuel, Alexander I Agoulnik, Ross AD Bathgate, Roger J Summers
Activation of the relaxin receptor RXFP1 has been associated with improved survival in acute heart failure. ML290 is a small molec..
The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1
Ashish Sethi, Shoni Bruell, Nitin Patil, Mohammed Akhter Hossain, Daniel J Scott, Emma J Petrie, Ross AD Bathgate, Paul R Gooley
H2 relaxin activates the relaxin family peptide receptor-1 (RXFP1), a class A G-protein coupled receptor, by a poorly understood m..
Native Chemical Ligation to Minimize Aspartimide Formation during Chemical Synthesis of Small LDLa Protein
Julien Tailhades, Ashish Sethi, Emma J Petrie, Paul R Gooley, Ross A Bathgate, John D Wade, Mohammed A Hossain
The inhibition of the G protein-coupled receptor, relaxin family peptide receptor 1 (RXFP1), by a small LDLa protein may be a pote..
Activation of relaxin family receptor 1 from different mammalian species by relaxin peptide and small-molecule agonist ML290
Zaohua Huang, Courtney Myhr, Ross AD Bathgate, Brian A Ho, Amaya Bueno, Xin Hu, Jingbo Xiao, Noel Southall, Elena Barnaeva, Irina U Agoulnik, Juan J Marugan, Marc Ferrer, Alexander I Agoulnik
Relaxin peptide (RLN), which signals through the relaxin family peptide 1 (RXFP1) GPCR receptor, has shown therapeutic effects in ..
Solution Structure, Aggregation Behavior, and Flexibility of Human Relaxin-2
Linda M Haugaard-Kedstrom, Mohammed Akhter Hossain, Norelle L Daly, Ross AD Bathgate, Ernst Rinderknecht, John D Wade, David J Craik, K Johan Rosengren
Relaxin is a member of the relaxin/insulin peptide hormone superfamily and is characterized by a two-chain structure constrained b..
Investigation of Interactions at the Extracellular Loops of the Relaxin Family Peptide Receptor 1 (RXFP1)
Natalie A Diepenhorst, Emma J Petrie, Catherine Z Chen, Amy Wang, Mohammed Akhter Hossain, Ross AD Bathgate, Paul R Gooley
Relaxin, an emerging pharmaceutical treatment for acute heart failure, activates the relaxin family peptide receptor (RXFP1), whic..
Mapping Key Regions of the RXFP2 Low-Density Lipoprotein Class-A Module That Are Involved in Signal Activation
Roy CK Kong, Ross AD Bathgate, Shoni Bruell, John D Wade, Paul R Gooley, Emma J Petrie
The peptide hormone INSL3 and its receptor, RXFP2, have co-evolved alongside relaxin and its receptor, RXFP1. Both RXFP1 and RXFP2..
The Relaxin Receptor (RXFP1) Utilizes Hydrophobic Moieties on a Signaling Surface of Its N-terminal Low Density Lipoprotein Class A Module to Mediate Receptor Activation
Roy CK Kong, Emma J Petrie, Biswaranjan Mohanty, Jason Ling, Jeremy CY Lee, Paul R Gooley, Ross AD Bathgate
The peptide hormone relaxin is showing potential as a treatment for acute heart failure. Although it is known that relaxin mediate..
Chimeric RXFP1 and RXFP2 Receptors Highlight the Similar Mechanism of Activation Utilizing Their N-Terminal Low-Density Lipoprotein Class A Modules.
Shoni Bruell, Roy CK Kong, Emma J Petrie, Brad Hoare, John D Wade, Daniel J Scott, Paul R Gooley, Ross AD Bathgate
Relaxin family peptide (RXFP) receptors 1 and 2 are unique G-protein coupled receptors in that they contain an N-terminal low-dens..