Allosteric modulation of mammalian c-type lectins

Session: 
S6.2 Lectins I
Code: 
OL6.2.3
Location (hall): 
Mannose
Start/end time: 
Tuesday, July 2, 2019 - 17:45 to 18:00
Christoph
Rademacher

Hengxi Zhang1, Phani Kumar Nekkanti2, Bettina Keller3, Marc Nazaré2Christoph Rademacher1

1Max Planck Institute Of Colloids And Interfaces, Potsdam, Germany, 2Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany, 3Freie Universität Berlin, Berlin, Germany

Many members of the C-type lectin family are expressed on cells of the innate immune system. These cell surface receptors promote pathogen recognition and, in some cases, also endocytosis. This recognition process is based on the interaction of the lectins with glycans found on the invading pathogen, often sufficient avidity is gained by homooligomerization of the receptor. On a molecular level, a central Ca2+ located in the carbohydrate binding site allows for the coordination of the glycan. Once endocytosed, this Ca2+ coordination can be perturbed by endosomal acidification and reduction of local Ca2+ concentration. While Ca2+ sequestering directly impairs carbohydrate recognition, pH-dependent loss of the receptor multimerization state results indirectly in cargo release in the endo-/lysosomal pathway. Taken together, C-type lectins harbor several molecular determinants in their overall architecture to promote pathogen binding, but also to enhance cargo release, rendering these receptors rather flexible on various time scales.

Here, we will summarize our efforts to make use of the structural plasticity of C-type lectins for the development of small molecule modulators of their receptor function. Previously, we have highlighted the discrepancy between the static picture of these proteins as inferred from X-ray crystallography and the experimental description of susceptibility of these proteins for drug-like molecule binding [1]. In particular, we found that besides the shallow and featureless carbohydrate recognition site, several secondary sites exist that are partially druggable and offer possibilities for inhibitor design against C-type lectins [2]. These insights are complemented by our studies into the receptor flexibility using protein NMR in combination with molecular dynamics simulations revealing an allosteric network of communicating amino acid sidechains. This network regulates the Ca2+ affinity and partially its pH sensitivity in human Langerin [3]. In summary, based on these insights on existence of druggable secondary sites and the presence of allostery, we were able to develop a series of allosteric inhibitors of murine Langerin in the low micromolar affinity regime [4]. 

References: 
  1. Aretz, J., Wamhoff, E.C., Hanske, J., Heymann, D., and Rademacher, C. (2014). Computational and experimental prediction of human C-type lectin receptor druggability. Frontiers in immunology 5, 323.
  2. Aretz, J., Baukmann, H., Shanina, E., Hanske, J., Wawrzinek, R., Zapol'skii, V.A., Seeberger, P.H., Kaufmann, D.E., and Rademacher, C. (2017). Identification of Multiple Druggable Secondary Sites by Fragment Screening against DC-SIGN. Angew Chem Int Ed Engl 56, 7292-7296.
  3. Hanske, J., Aleksic, S., Ballaschk, M., Jurk, M., Shanina, E., Beerbaum, M., Schmieder, P., Keller, B.G., and Rademacher, C. (2016). Intradomain Allosteric Network Modulates Calcium Affinity of the C-Type Lectin Receptor Langerin. J Am Chem Soc 138, 12176-12186.
  4. Aretz, J., Anumala, U.R., Fuchsberger, F.F., Molavi, N., Ziebart, N., Zhang, H., Nazare, M., and Rademacher, C. (2018). Allosteric Inhibition of a Mammalian Lectin. J Am Chem Soc 140, 14915-14925.

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