Biochemistry and Pharmacology - Research Publications

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Start date: 2012 × Author: HOSSAIN, MOHAMMED × Author: Bathgate, Ross × End date: 2016 ×

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    The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1
    Sethi, A ; Bruell, S ; Patil, N ; Hossain, MA ; Scott, DJ ; Petrie, EJ ; Bathgate, RAD ; Gooley, PR (NATURE PUBLISHING GROUP, 2016-04)
    H2 relaxin activates the relaxin family peptide receptor-1 (RXFP1), a class A G-protein coupled receptor, by a poorly understood mechanism. The ectodomain of RXFP1 comprises an N-terminal LDLa module, essential for activation, tethered to a leucine-rich repeat (LRR) domain by a 32-residue linker. H2 relaxin is hypothesized to bind with high affinity to the LRR domain enabling the LDLa module to bind and activate the transmembrane domain of RXFP1. Here we define a relaxin-binding site on the LDLa-LRR linker, essential for the high affinity of H2 relaxin for the ectodomain of RXFP1, and show that residues within the LDLa-LRR linker are critical for receptor activation. We propose H2 relaxin binds and stabilizes a helical conformation of the LDLa-LRR linker that positions residues of both the linker and the LDLa module to bind the transmembrane domain and activate RXFP1.
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    The Importance of Tryptophan B28 in H2 Relaxin for RXFP2 Binding and Activation
    Chan, LJ ; Wade, JD ; Separovic, F ; Bathgate, RAD ; Hossain, MA (SPRINGER, 2013-03)
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    The C-terminus of the B-chain of human insulin-like peptide 5 is critical for cognate RXFP4 receptor activity
    Patil, NA ; Bathgate, RAD ; Kocan, M ; Ang, SY ; Tailhades, J ; Separovic, F ; Summers, R ; Grosse, J ; Hughes, RA ; Wade, JD ; Hossain, MA (SPRINGER WIEN, 2016-04)
    Insulin-like peptide 5 (INSL5) is an orexigenic peptide hormone belonging to the relaxin family of peptides. It is expressed primarily in the L-cells of the colon and has a postulated key role in regulating food intake. Its G protein-coupled receptor, RXFP4, is a potential drug target for treating obesity and anorexia. We studied the effect of modification of the C-terminus of the A and B-chains of human INSL5 on RXFP4 binding and activation. Three variants of human INSL5 were prepared using solid phase peptide synthesis and subsequent sequential regioselective disulfide bond formation. The peptides were synthesized as C-terminal acids (both A- and B-chains with free C-termini, i.e., the native form), amides (both chains as the C-terminal amide) and one analog with the C-terminus of its A-chain as the amide and the C-terminus of the B-chain as the acid. The results showed that C-terminus of the B-chain is more important than that of the A-chain for RXFP4 binding and activity. Amidation of the A-chain C-terminus does not have any effect on the INSL5 activity. The difference in RXFP4 binding and activation between the three peptides is believed to be due to electrostatic interaction of the free carboxylate of INSL5 with a positively charged residue (s), either situated within the INSL5 molecule itself or in the receptor extracellular loops.