PDBsum entry 2k1v

Hormone

PDB id: 2k1v

Contents

Protein chains

27 a.a.

22 a.a.

PDB id:

2k1v

Name:

Hormone

Title:

R3/i5 relaxin chimera

Structure:

Relaxin-3. Chain: b. Fragment: relaxin-3 b chain. Synonym: prorelaxin h3, insulin-like peptide insl7, insulin-like peptide 7. Engineered: yes. Insulin-like peptide insl5. Chain: a. Fragment: insulin-like peptide insl5 a chain.

Source:

Synthetic: yes. Other_details: peptide chain was assembled by solid phase peptide synthesis.. Synthesis.

NMR struc:

20 models

Authors:

K.Rosengren,L.M.Haugaard-Jonsson

Key ref:

L.M.Haugaard-Jönsson et al. (2008). Structure of the R3/I5 chimeric relaxin peptide, a selective GPCR135 and GPCR142 agonist. J Biol Chem, 283, 23811-23818. PubMed id: 18577524 DOI: 10.1074/jbc.M800489200

Date:

17-Mar-08 Release date: 08-Apr-08

Protein chain

Q8WXF3  (REL3_HUMAN) -  Relaxin-3 from Homo sapiens

Seq: 142 a.a.

Struc: 27 a.a.

Protein chain

Q9Y5Q6  (INSL5_HUMAN) -  Insulin-like peptide INSL5 from Homo sapiens

Seq: 135 a.a.

Struc: 22 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1074/jbc.M800489200

J Biol Chem 283:23811-23818 (2008)

PubMed id: 18577524

Structure of the R3/I5 chimeric relaxin peptide, a selective GPCR135 and GPCR142 agonist.

L.M.Haugaard-Jönsson, M.A.Hossain, N.L.Daly, R.A.Bathgate, J.D.Wade, D.J.Craik, K.J.Rosengren.

ABSTRACT

The human relaxin family comprises seven peptide hormones with various biological functions mediated through interactions with G-protein-coupled receptors. Interestingly, among the hitherto characterized receptors there is no absolute selectivity toward their primary ligand. The most striking example of this is the relaxin family ancestor, relaxin-3, which is an agonist for three of the four currently known relaxin receptors: GPCR135, GPCR142, and LGR7. Relaxin-3 and its endogenous receptor GPCR135 are both expressed predominantly in the brain and have been linked to regulation of stress and feeding. However, to fully understand the role of relaxin-3 in neurological signaling, the development of selective GPCR135 agonists and antagonists for in vivo studies is crucial. Recent reports have demonstrated that such selective ligands can be achieved by making chimeric peptides comprising the relaxin-3 B-chain combined with the INSL5 A-chain. To obtain structural insights into the consequences of combining A- and B-chains from different relaxins we have determined the NMR solution structure of a human relaxin-3/INSL5 chimeric peptide. The structure reveals that the INSL5 A-chain adopts a conformation similar to the relaxin-3 A-chain, and thus has the ability to structurally support a native-like conformation of the relaxin-3 B-chain. These findings suggest that the decrease in activity at the LGR7 receptor seen for this peptide is a result of the removal of a secondary LGR7 binding site present in the relaxin-3 A-chain, rather than conformational changes in the primary B-chain receptor binding site.

Selected figure(s)

Figure 4.
FIGURE 4. Comparison of the structures of the R3/I5 chimera (blue) and native relaxin-3 (pink). The structures are overlaid and shown in ribbon representation to illustrate the positions of the three helical segments. Key amino acids in the hydrophobic core and active site are shown in ball- and stick representation and labeled with residue numbers. The INSL5 A-chain is three residues shorter at the N terminus, which results in a shorter helical segment that is slightly tilted in relation to the C-terminal helix. In contrast in relaxin-3 the two A-chain helical segments are roughly parallel.

Figure 5.
FIGURE 5. Electrostatic surfaces of the NMR structures of relaxin-3 (a) and R3/I5 (b), and the crystal structure of relaxin-2 (c). A ribbon representation of the structures in the same orientation as in the central panels is shown to the left for clarity. Views in the right-hand side panel are rotated 180° in relation to the views in the central panel. Positively and negatively charged residues are colored red and blue, respectively, and hydrophobic residues are shown in green. Selected residues are labeled with chain identifiers and residue numbers.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 23811-23818) copyright 2008.

Figures were selected by an automated process.