ÀÖÌìÌÃÓÎÏ·ÍøÕ¾

December’s marvellous featured artwork in our 2019 PDBe calendar raises an apposite question surrounding the origins of greatness, drawing inspiration from the Human growth hormone somatotropin; molecules or morals. It’s surely not black and white, but is it ever red, white, and blue?

What maketh the man

Somatotropin, otherwise known as human growth hormone (GH), is a signalling molecule, secreted by the pituitary gland, which is involved in the regulation of cellular growth and reproduction. It therefore plays a crucial role during childhood development where it drives progressive change in many characteristics such as height, bone strength, muscle mass, metabolism, and immunity... important attributes for any budding superhero. 

In healthy individuals, somatotropin is secreted into the bloodstream, where its natural function is to trigger cellular signalling pathways by interacting with membrane protein receptors all over the body. Interestingly, different variants of the same GH gene have been shown to exist which may have distinct roles, for example in gestation compared to following exercise. 

Somatotropin also has a crucial part to play once we’re fully grown. Whilst only around half the amount of GH is normally made in adulthood compared to adolescence, it’s just as necessary for the correct maintenance of all the aforementioned traits, and it even has links to positive mental health. 

With great power...

In fact, somatotropin is so important to animal development (not just us humans!), that irregular GH production can very quickly give rise to a wide range of maladies. 

Aberrant levels of somatropin can occur at any stage of life. Congenital GH deficiency can be due to direct genetic factors, whereas issues later in life are typically associated with damage to the pituitary gland and its related tissues from trauma or infection. The immediate consequence of childhood GH deficiency tends to be limited height. Fortunately, treatment with synthetic GH injections has been available since the 1980s and is effective and well tolerated. On the other hand, adults who suffer from GH deficiency may experience fatigue, decreased muscle mass, weight gain, and will also have a higher risk of developing heart disease and diabetes.

The effects of unusually high levels of somatropin on the other hand, whilst thankfully much rarer, can result in more severe physical symptoms. In children, too much GH causes gigantism which can result in symptoms such as abnormal height, joint pain, poor peripheral vision, large hands and feet, prominent facial features, and insomnia. The analogous condition in adults (acromegaly) can lead to a similar range of symptoms. For both adults and children, the predominant cause of GH overproduction are benign tumours affecting the pituitary gland.  

...comes great responsibility

However, the potent effects of GH have not gone unnoticed. After synthetic GH became medically available ~30 years ago, its popularity has continued to grow amongst amateur and professional athletes alike. Yet whilst the use of GH is banned in international sport, and in spite of the immediate risks associated with needle use and the longer-term risks leading to acromegaly, the promise of increased muscle mass, improved recovery times, and enhanced fat metabolism seems to be too tempting for some. Indeed, not only are the effects measurable, but because synthetic GH is all but identical to the naturally occurring protein and because natural GH secretion can vary significantly over time, abnormal levels are extremely difficult to detect. 

Somatotropin

The structure of Human somatropin (Figure 1) is made of 191 amino acids. The core fold is comprised of a four-helix bundle, termed a long-helix cytokine, and 3 shorter helices decorate the exterior. The four main helices run anti-parallel and form a dense hydrophobic core which helps to stabilise the fold with abundant hydrogen bonding and salt bridges. Two disulphide bonds further stabilise the structure by confining both the helix 1-to-2 loop and the flexible C-terminus to the protein core.

The structure of mutant Human growth hormone somatotropin (PDB: 1HUW). The left-hand chain is shown in space-filling atoms, whilst the centre chain is shown in blue cartoon helices. The surface representation of the right-hand chain is coloured by electrostatic charge (+/-).

Interestingly, the model presented in Figure 1 which inspired this month’s artwork has 15 mutations in its amino acid sequence compared to wild-type Human somatotropin. Whilst these changes were not shown to significantly alter the structure of the protein, many of the mutations led to changes in the exposed chemical groups on the protein surface that enhanced somatotropins affinity for its natural binding partner by 400-fold!

This protein therefore has the potential to make us great, yet can now be made even greater still. Thanks to our growing understanding of how these molecules work, our ability to enhance the function of natural proteins is becoming more commonplace and will raise ethical questions about how we choose to use them in future applications.

About the artwork

December’s artwork was created digitally by Emi Rush from . Inspiration was taken from the X-ray structure of somatotropin (1HUW) published in 1994 by Ultsch et al.

James Tolchard