Press Release
Structural Biology
08.07.2019

Helmholtz researchers decode the mechanism of new small molecule inhibitors for the treatment of depression, pain and obesity

Researchers at the Helmholtz Zentrum München have moved a step closer towards developing innovative drug molecules for the treatment of psychiatric diseases. They discovered how inhibitors inactivate a special protein that plays a key role in various diseases. Their approach can be applied to other medically relevant proteins where the development of specific inhibitors has proved difficult up to now.

Figure adapted. © 2019, John Wiley and Sons Inc.

At first sight, depression, chronic pain and obesity appear to be separate diseases. However, various studies have shown that a protein named FKBP51 plays a key role in all three disorders. Consequently, the FKBP51 protein was already recognized as a target structure for pharmaceutical therapy.

There is only one catch: FKBP51 cannot simply be inhibited by a small molecule because its receptor antagonist, protein FKBP52, is too similar in structure. Whereas FKBP52 increases the activity of glucocorticoid receptors**, FKBP51 has an inhibiting effect on them. Glucocorticoid receptors are the stress hormone receptors in the brain. Prolonged activation of these receptors can lead to psychiatric diseases. Development of a selective inhibitor that can differentiate between both proteins and selectively inhibit only one of them is therefore crucial for developing drug molecules without unwanted side effects. Or to use another analogy, it is rather like having to develop a specific key that only fits into the FKBP51 keyhole, but not into the FKBP52 one.

Back in 2014, Felix Hausch from the Max Planck Institute for Psychiatry developed the highly specific inhibitor SAFit in order to switch off the FKBP51 protein but not FKBP52***. “The underlying mechanism for the selectivity was, however, unknown,” says Professor Michael Sattler, Director of the Institute of Structural Biology at the Helmholtz Zentrum München and the Technical University of Munich (TUM).

What effect do inhibitors have on FKBP51?

In order to clarify this question, Prof. Sattler and his colleagues combined different methods. With the aid of nuclear magnetic resonance (NMR) spectroscopy, the internal mobility of the FKBP51 protein was determined in order to examine what role this plays for the SAFit inhibitor. In addition, they carried out biophysical measurements to determine the affinity and kinetic binding rates that lead to binding, and also performed mutation analyses. If individual letters (nucleotides) in the corresponding gene are replaced, proteins with specific amino acid changes and thus different properties are produced. It can thus be seen which of the protein’s amino acids are required in order to promote the binding of an inhibitor to the target protein.

“We discovered that SAFit molecules bind to a transient pocket in FKBP51 that is normally hidden and not accessible,” Sattler reports. “The binding site is blocked by an amino acid and is only accessible in fewer than 1% of all molecules. However, NMR experiments demonstrated that the blocking amino acid is dynamic and sometimes allows access to the binding cavity. SAFit molecules can now exploit this for binding to the pocket. Once bound, the inhibitor then inactivates the FKBP51 protein. As no such dynamic pocket exists in FKBP52, the SAFit inhibitors cannot bind to this protein.

Sattler speaks of a “crucial step” in the development of new drugs. “The concept that has been discovered here and our methodology can now be applied to other proteins where it is difficult to develop selective inhibitors,” he notes. “This will open up new possibilities for many diseases with unmet medical needs.”

The research teams led by Felix Hausch, now at TU Darmstadt, and Michael Sattler will now continue with their approach and develop the concept as part of a LOEWE research proposal, which has just been approved by the federal state of Hesse.

Further information

Original publication: Jagtap PKA et al, Selective inhibitors of FKBP51 employ conformational selection of dynamic invisible, Angewandte Chemie International Edition, Doi: 10.1002/anie.201902994.

* Sources: Balsevich et al, Nat Commun 2017,
https://www.nature.com/articles/s41467-017-01783-y

Maiaru et al, Sci Transl Med 2016, https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/26865567/ 

** Glucocorticoid receptors are binding sites for steroid hormones.

*** Quelle: https://www.psych.mpg.de/2017580/PM1410

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,500 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 19 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. 

The Institute for Structural Biologyinvestigates the spatial structures of biological macromolecules, analyses their structure and dynamics and develops NMR-spectroscopy methods for carrying out these studies. Its goal is to illuminate the structural and molecular mechanisms and their role in disease. The structural data form the basis for the rational design and development of small molecular inhibitors in combination with chemical and biological approaches. http://www.helmholtz-muenchen.de/stb

The Technical University of Munich (TUM) is one of Europe’s leading research universities, with around 550 professors, 41,000 students, and 10,000 academic and non-academic staff. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, combined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with the TUM Asia campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany.

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