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Laboratory of Biomolecular Research

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Prof. Dr. Volodymyr Korkhov

Photo of Volodymyr Korkhov

Group Leader

Paul Scherrer Institute
Forschungsstrasse 111
5232 Villigen PSI
Switzerland
Telefon
+41 56 310 28 42
E-Mail
volodymyr.korkhov@psi.ch

Research Interests

Interactions between the cell and its environment, as well as between different cellular compartments, occur at the biological membranes. Extracellular signals are sensed by the receptors at the cell surface. These signals are then transmited across the membrane via multiple biomolecular interactions involving membrane-bound and soluble proteins, resulting in complex biochemical responses inside the cell. The process of signal transduction is critically important for physiology in health and disease. The research in my group is focused on understanding the molecular mechanisms of signal transduction. Using a multidisciplinary approach including methods of membrane protein biochemistry, biophysics and structural biology (including X-ray crystallography and cryo-EM), we aim to understand the structure-function relationships of membrane proteins and protein complexes involved in various aspects of cellular signalling. We are particularly interested in membrane protein complexes in two areas of signalling: (i) the cyclic adenosine monophosphate (cAMP) pathway, (ii) the Hedgehog signalling pathway.
 

Research Highlights

1. Cryo-EM structure of membrane adenylyl cyclase-G protein complex

hl1_korkhov

The structure of adenylyl cyclase-9 (AC9) bound to an activated G protein as subunit, solved at a resolution of 3.4 Å by cryo-EM and single particle analysis, reveals the organization of a complete AC-Ga protein complex. The structure features the key domains of the membrane AC: the membrane domain, the cytosolic catalytic domain, and the helical domain that connects the membrane and the catalytic portions of AC9. The structure also features a C-terminal peptide occluding the catalytic and allosteric sites of AC9. The occluded state of the AC is distinct from its substrate- and activator-bound state. The structural and biochemical evidence provides new insights into the auto-regulatory function of the C-terminus. The natural ligand for the AC allosteric site has until now remained unknown, and thus the results hint at the potential physiological role of the allosteric site of the membrane ACs in direct protein-protein interactions. Similar modes of regulation may apply to other membrane ACs.

Qi et al., Science, 2019

https://science.sciencemag.org/content/364/6438/389


2. Cryo-EM structure of the human PTCH1 bound to a modified Sonic Hedgehog ligand

 

hl2_korkhov

The Hedgehog signalling pathway has an important role in tissue patterning during embryonic development and is linked to human disease. Binding of Sonic Hedgehog morphogen, Shh, to PTCH1 initiates the Hedgehog signalling cascade. PTCH1 has been suggested to act as a transporter for cholesterol, and this transport activity apparently underlies its role in controlling the Hedgehog pathway. We have determined the 3.4 Å resolution structure of PTCH1 bound to a Hedgehog ligand variant ShhNC24II using cryo-EM and single particle analysis. A set of sterol molecules was observed bound in positions within the outer and inner leaflet of the membrane at the Sterol Sensing Domain (SSD) and the SSD-like domain of PTCH1. The structure suggests a possible route for sterol translocation across the lipid bilayer mediated by PTCH1 and related transporters.

Qi et al., Sci Adv, 2019

https://advances.sciencemag.org/content/5/9/eaaw6490


Key Publications

1. Vercellino I. Rezabkova L., Olieric V., Polyhach Y., Weinert T., Kammerer R.A., Jeschke G., Korkhov V.M. Role of the nucleotidyl cyclase helical domain in catalytically active dimer formation. Proc Natl Acad Sci U S A. (2017) 114, E9821-E9828.

2. Qi C., Sorrentino S., Medalia O., Korkhov V.M. The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein. Science (2019) 364, 389-394.

3. Qi C., Di Minin G., Vercellino I., Wutz A., Korkhov V.M. Structural basis of sterol recognition by human hedgehog receptor PTCH1. Sci Adv (2019) 5(9), eaaw6490.

4. Cannac F., Qi C., Falschlunger J., Hausmann G., Basler K., Korkhov V.M. Cryo-EM structure of the Hedgehog release protein Dispatched. (2019) bioRxiv, doi: https://doi.org/10.1101/707513

Group Members

Photo of Volodymyr Korkhov
Prof. Dr. Volodymyr Korkhov

Group Leader

+41 56 310 28 42
volodymyr.korkhov@psi.ch
Photo of Chao Qi
Chao Qi

Postdoc

+41 56 310 50 63
chao.qi@psi.ch
foto
Basavraj Khanppnavar

Postdoc

+41 56 310 46 98
basavraj.khanppnavar@psi.ch
Photo of Ved Mehta
Ved Jaimini Mehta

Ph.D Student

+41 56 310 50 63
ved.mehta@psi.ch
Dina Schuster

Ph.D Student

+41 56 310 29 80
dina.schuster@psi.ch
Pia Lavriha

Master Student

+41 56 310 50 63
pia.lavriha@psi.ch

Former Members


Weinert, Adriana (Postdoc)


Vercellino,Irene (Ph.D. Student)


Graeber,Elisabeth (Ph.D. Student)


Cannac, Fabien (Ph.D Student)


Oezel, Merve (Master/Ph.D Student)


korkhov_group_2020

Publications

  • Cannac F, Qi C, Falschlunger J, Hausmann G, Basler K, Korkhov VM
    Cryo-EM structure of the Hedgehog release protein Dispatched
    Science Advances. 2020; 6(16): eaay7928 (8 pp.). https://doi.org/10.1126/sciadv.aay7928
    DORA PSI
  • Graeber E, Korkhov VM
    Affinity purification of membrane proteins
    In: Perez C, Maier T, eds. Expression, purification, and structural biology of membrane proteins. Methods in molecular biology. New York: Humana; 2020:129-137. https://doi.org/10.1007/978-1-0716-0373-4_9
    DORA PSI
  • Khannpnavar B, Mehta V, Qi C, Korkhov V
    Structure and function of adenylyl cyclases, key enzymes in cellular signaling
    Current Opinion in Structural Biology. 2020; 63: 34-41. https://doi.org/10.1016/j.sbi.2020.03.003
    DORA PSI
  • Graeber E, Korkhov VM
    Characterisation of the ligand binding sites in the translocator protein TSPO using the chimeric bacterial-mammalian constructs
    Protein Expression and Purification. 2019; 164: 105456 (10 pp.). https://doi.org/10.1016/j.pep.2019.105456
    DORA PSI
  • Qi C, Minin GD, Vercellino I, Wutz A, Korkhov VM
    Structural basis of sterol recognition by human hedgehog receptor PTCH1
    Science Advances. 2019; 5(9): eaaw6490 (9 pp.). https://doi.org/10.1126/sciadv.aaw6490
    DORA PSI
  • Qi C, Sorrentino S, Medalia O, Korkhov VM
    The structure of a membrane adenylyl cyclase bound to an activated stimulatory G protein
    Science. 2019; 364(6438): 389-394. https://doi.org/10.1126/science.aav0778
    DORA PSI
  • Graeber E, Korkhov VM
    Expression and purification of the mammalian translocator protein for structural studies
    PLoS One. 2018; 13(6): e0198832 (17 pp.). https://doi.org/10.1371/journal.pone.0198832
    DORA PSI
  • Mireku SA, Ruetz M, Zhou T, Korkhov VM, Kräutler B, Locher KP
    Conformational change of a tryptophan residue in BtuF facilitates binding and transport of cobinamide by the vitamin B12 transporter BtuCD-F
    Scientific Reports. 2017; 7: 41575 (11 pp.). https://doi.org/10.1038/srep41575
    DORA PSI
  • Vercellino I, Rezabkova L, Olieric V, Polyhach Y, Weinert T, Kammerer RA, et al.
    Role of the nucleotidyl cyclase helical domain in catalytically active dimer formation
    Proceedings of the National Academy of Sciences of the United States of America PNAS. 2017; 114(46): E9821-E9828. https://doi.org/10.1073/pnas.1712621114
    DORA PSI
  • Korkhov VM, Mireku SA, Veprintsev DB, Locher KP
    Structure of AMP-PNP-bound BtuCD and mechanism of ATP-powered vitamin B12 transport by BtuCD-F
    Nature Structural and Molecular Biology. 2014; 21(12): 1097-1099. https://doi.org/10.1038/nsmb.2918
    DORA PSI
  • Chen F, Gerber S, Heuser K, Korkhov VM, Lizak C, Mireku S, et al.
    High-mass matrix-assisted laser desorption ionization-mass spectrometry of integral membrane proteins and their complexes
    Analytical Chemistry. 2013; 85(7): 3483-3488. https://doi.org/10.1021/ac4000943
    DORA PSI
  • Korkhov VM, Mireku SA, Hvorup RN, Locher KP
    Asymmetric states of vitamin B 12 transporter BtuCD are not discriminated by its cognate substrate binding protein BtuF
    FEBS Letters. 2012; 586(7): 972-976. https://doi.org/10.1016/j.febslet.2012.02.042
    DORA PSI
  • Korkhov VM, Mireku SA, Locher KP
    Structure of AMP-PNP-bound vitamin B 12 transporter BtuCD-F
    Nature. 2012; 490(7420): 367-372. https://doi.org/10.1038/nature11442
    DORA PSI

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Laboratory of Biomolecular Research

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Anita Strittmatter
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Paul Scherrer Institut
Department of Biology and Chemistry
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Forschungsstrasse 111
CH-5232 Villigen PSI
Switzerland

Phone: +41 56 310 20 35
Fax: +41 56 310 21 99
anita.strittmatter@psi.ch

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