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Laboratory of Structural Biology

Principal Investigator: Václav Veverka, Ph.D.

ORCID iD iconorcid.org/0000-0003-3782-5279

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Research focus:

We use the means of integrative structural biology for detailed understanding of various biological processes. We focus on validation of biomolecular interactions that play important roles in human pathologies and can be exploited for therapeutic intervention. In a joint effort with medicinal chemists we develop small molecule inhibitors for these interactions. We study protein interaction networks that are implicated in regulation of gene transcription and also contribute to development of haematological malignancies. One of them is the iteractome of an epigenetic reader LEDGF/p75 that tethers other factors to the actively transcribed genes on chromatin. Its activity is essential for development of the two distinct diseases: HIV infection and Mixed-lineage leukemia (MLL).

 


 

The LEDGF/p75 interaction network. LEDGF/p75 recognizes its interaction partners – HIV integrase  (HIV IN) and cellular factors -  through the Integrase Binding Domain (IBD). Cellular proteins interact with the IBD through a conserved intrinsically disordered motif (Tesina et al. 2016 Nat commun).

 


 

LEDGF/p75 IBD binding partners interact in a structurally conserved manner. A) Multiple sequence alignment illustrating the conserved LEDGF/p75 IBD binding motif. (B) Detail of the POGZ-LEDGF/p75 interface from the obtained solution structure. (C) Solution structures of the IBD in complex with the binding motifs from cellular binding partners (Sharma et al. 2018 PNAS).

 


Graduate students:

Eliška Koutná eliska.koutna@uochb.cas.cz

Project: Biological roles of LEDGF/p75 (since 2018)

Lenka Vaneková lenka.vanekova@uochb.cas.cz

Project: Modulation of the STING signaling pathway (since 2018)

Lisa-Maria Weinhold lisa-maria.weinhold@uochb.cas.cz

Project: Structural relationship between subunits of chromatin remodeling complexes (since 2019)

 

Undergraduate students:

Karolína Naušová

Project: Detailed characterization of the interaction between LEDGF/p75 and MeCP2 (def. 2020)

 

Alumni:

Rozálie Hexnerová, Ph.D. rozalie.hexnerova@uochb.cas.cz

Project: Structural NMR studies of metabolically active proteins (def. 2019)

 

Teaching comitment:

Practical Course in Structural Biology (MC250P76)

Structural Biology of the Cell (MB151P117)

Determination of the 3D structure of macromolecules (MC250P17)

Advanced NMR methods (MC270P08A)

 

Selected papers:

Sharma, S. et al. Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation. Proc Natl Acad Sci U S A 115, E7053-E7062 (2018).

Hodges, H.C. et al. Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers. Nat Struct Mol Biol 25, 61-72 (2018).

Hnízda, A. et al. Relapsed acute lymphoblastic leukemia-specific mutations in NT5C2 cluster into hotspots driving intersubunit stimulation. Leukemia 32, 1393-1403 (2018).

Hnízda, A. et al. Oligomeric interface modulation causes misregulation of purine 5 -nucleotidase in relapsed leukemia. BMC Biol 14, 91 (2016).

Těšina, P. et al. Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif. Nat Commun 6, 7968 (2015).

Čermáková, K. et al. Validation and structural characterization of the LEDGF/p75-MLL interface as a new target for the treatment of MLL-dependent leukemia. Cancer Res 74, 5139-51 (2014).

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