A Surprising Message from Murines

Abstract

Rat relaxin had been known for about 18 years and had been thoroughly characterized mainly through by Sherwood et al.^1–4 The relaxin used in those studies had been isolated by the method of Walsh et al in which homogenized ovaries were extracted with a mixture of trifluoroacetic acid (15%), formic acid (5%), sodium chloride (1%) and hydrochloric acid (1M).^5,6 The conditions seemed rather rough but an active hormone was obtained which was used for all subsequent studies until very recently. Rat relaxin (Fig.13.1), always considered to be a relaxin of low potency, made a natural connection to our structure function studies, in particular the beneficial effect of replacement of histidine B10 in insulaxin for a glutamic acid. In the rat this position was occupied by glycine and based on a central dogma in protein chemistry, this was an unfavorable situation. Glycine is considered a helix-breaking residue and its presence in the major B chain helix right at the receptor interaction site seemed a clear indication that glycine B14 was compromising the bioactivity of rat relaxin. The opportunity was irresistible to test one’s ability to predict how certain features in a molecule would influence its bioactivity and subsequently to improve on a natural product. First rat relaxin was needed to establish a baseline and consequently a few milligrams were synthesized by the new method.⁷