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Protein design of growth factor inhibitors

MPS-Authors
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Maksymenko,  K
Department Protein Evolution, Max Planck Institute for Biology Tübingen, Max Planck Society;

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Lupas,  AN
Department Protein Evolution, Max Planck Institute for Biology Tübingen, Max Planck Society;

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ElGamacy,  M
Department Protein Evolution, Max Planck Institute for Biology Tübingen, Max Planck Society;

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Citation

Maksymenko, K., Müller, P., Skokowa, J., Lupas, A., & ElGamacy, M. (2022). Protein design of growth factor inhibitors. In Advances in Protein Folding, Evolution and Design (APFED 2022) (pp. 29).


Cite as: https://hdl.handle.net/21.11116/0000-000A-E137-A
Abstract
Growth factors are signaling molecules coordinating the complex functionality of multicellular
organisms during development and homeostasis. Since aberrant expression of growth factors can
cause diverse disorders such as cancer, autoimmune and cardiovascular diseases, growth factors and
their receptors are central targets for therapeutic modulation. One of the options to manipulate
signaling interactions is to use protein-based binders that are highly specific and able to target various
molecular surfaces. Here, we present two different strategies of computational protein design to obtain
inhibitors against growth factors which are key modulators of tumor progression. The first approach
requires the structure of a native growth factor:growth factor receptor complex and aims to re-engineer
a natural binding domain to make it more soluble, more stable, or more affine. In contrast, the second
approach relies only on the structure of a target epitope and takes advantage of new software for
massive-scale docking of a target site against a protein structure database to select the high shape
complementary scaffolds. Adopting the first approach, we designed inhibitors of epidermal growth
factor (EGF) using a single domain of EGF receptor as a template. Experimental evaluation of only two
designed candidates revealed that both of them are solubly expressed, stable, and bind EGF with
nanomolar affinities (i.e. 5-fold stronger than a native domain). Furthemore, we showed that one design
inhibits EGF-induced proliferation of epidermoid carcinoma cells with IC50 of 0.5 nM. Using the second
strategy, we designed inhibitors of vascular endothelial growth factor (VEGF) based on two different
scaffolds. The binding affinities of the designs (16 candidates) to VEGF range from nano- to micromolar
levels. X-ray structure determination of one of the candidates showed atomic-level agreement with the
design model. Moreover, the best designs showed the ability to inhibit proliferation of VEGF-dependent
cells. Thus, our results demonstrate the feasibility of the rational and generalizable approaches to design high-affinity protein binders against predefined conformational motifs.