Our favorite papers

Here are the five papers that I think represent our biggest, most significant contributions:

 
 
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Architectures of lipid transport systems for the bacterial outer membrane

Damian C. Ekiert*, Gira Bhabha*, Georgia L. Isom, Garrett Greenan, Sergey Ovchinnikov, Ian R. Henderson, Jeffery S. Cox, Ronald D. Vale

Here we report the first structural characterization of MCE proteins, which are broadly conserved among double-membraned bacteria and at least some eukaryotic organelles.  These structures reveal that some MCE proteins form long tubes and needle-and-syringe like architectures, which we proposed form bridges across the periplasm that mediate the transport of lipids between the bacterial inner and outer membranes.

Cell 2017 (In press).

Check out the pre-print on BioRxiv!


Structure of a PE-PPE-EspG complex from Mycobacterium tuberculosis reveals molecular specificity of ESX protein secretion

Damian C. Ekiert and Jeffery S. Cox

Here we reported the crystal structures of EspG3 and EspG5, proteins implicated in the function of the ESX/type VII secretion systems of M. tuberculosis.  We showed that EspG3 and EspG5 interact with distinct subsets of the highly expanded protein families PE and PPE, which are secreted through ESX.  By determining the crystal structures of EspG5 in complex with a PE-PPE heterodimer, we were able to map the surfaces of EspG and PPE important for the interaction and predict which PPE substrates would be secreted through each ESX system M. tuberculosis.

Proc Natl Acad Sci USA 2014.  Download PDF.

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Reshaping antibody diversity

Feng Wang*, Damian C. Ekiert*, Insha Ahmad, Wenli Yu, Yong Zhang, Omar Bazirgan, Ali Torkamani, Terje Raudsepp, Waithaka Mwangi, Michael F. Criscitiello, Ian A. Wilson, Peter G. Schultz, Vaughn V. Smider

The antibody CDR H3 loop (Heavy chain Complementarity Determining Region 3) is highly variable and dominates most antibody-antigen interactions.  While in mice CDR H3 might be just 5-10 residues long, in cattle this loop can be nearly 70 residues long and rich in cysteines.  To understand how these unique antibodies recognize antigens, we determined the crystal structures of two such bovine antibodies.  The structures revealed a remarkable, disulfide-stabilized "ball-and-chain"-like architecture extending far from the conventional antigen binding site, and we showed that the "ball" mediated antigen binding.  Like the discovery of camelid and shark IgNAR antibodies that completely lack conventional light chains, this work revealed a completely new mechanism of antigen recognition.

Cell 2013.  Download PDF.


A highly conserved neutralizing epitope on group 2 influenza A viruses

Damian C. Ekiert, Robert H. E. Friesen, Gira Bhabha, Ted Kwaks, Mandy Jongeneelen, Wenli Yu, Carla Ophorst, Freek Cox, Hans J.W.M. Korse, Boerries Brandenburg, Ronald Vogels, Just P.J. Brakenhoff, Ronald Kompier, Martin H. Koldijk, Lisette A.H.M. Cornelissen, Leo L. M. Poon, Malik Peiris, Wouter Koudstaal, Ian A. Wilson, Jaap Goudsmit

Following on our earlier work on a broadly neutralizing antibody against influenza, here we identified and characterized a second broadly neutralizing antibody (CR8020) targeting a second site of vulnerability on the hemagglutinin stem.  Crystal structures, along with biochemical, cull-culture based, and in vivo studies unraveled the specificity, mechanism of action, and therapeutic potential of this new antibody and it promise to guide vaccine design.  Along with the previously identified CR6261, these two antibodies provide complete protection against the vast majority of influenza A viruses.

Science 2011.  Download PDF.

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Antibody recognition of a highly conserved influenza virus epitope

Damian C. Ekiert, Gira Bhabha, Marc-Andre Elsliger, Robert H. Friesen, Mandy Jongeneelen, Mark Throsby, Jaap Goudsmit, and Ian A. Wilson

Most antibodies against influenza are strain specific, which makes the development effective, long-lasting vaccines very difficult.  In this paper we describe the crystal structure of one of the first broadly neutralizing antibodies against flu (CR6261), in a complex with its target antigen, hemagglutinin.  The structure revealed a previously unrecognized site of vulnerability on hemagglutinin that is highly conserved across most strains.  Our understanding of this antibody antigen interaction has served as a road map for the development of promising new antibody therapies and improved, universal vaccines.

Science 2009.  Download PDF.


 

All Publications

 
  1. Ekiert DC*, Bhabha G*, Isom GL, Greenan G, Ovchinnikov S, Henderson IR, Cox JS, Vale RD. Architectures of lipid transport systems for the bacterial outer membrane.
    Cell. 2017.  In press.
    Read the pre-print posted on BioRxiv July 18, 2016.

  2. Brunette TJ, Parmeggiani F, Huang PS, Bhabha G, Ekiert DC, Tsutakawa SE, Hura GL, Tainer JA, Baker D. Exploring the repeat protein universe through computational protein design.
    Nature. 2015 Dec 24;528(7583):580-4Download PDF.

  3. Ekiert DC, Cox JS. Structure of a PE-PPE-EspG complex from Mycobacterium tuberculosis reveals molecular specificity of ESX protein secretion.
    Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):14758-63Download PDF.

  4. Liu Y, Zhang X, Tan YL, Bhabha G, Ekiert DC, Kipnis Y, Bjelic S, Baker D, Kelly JW. De novo-designed enzymes as small-molecule-regulated fluorescence imaging tags and fluorescent reporters.
    J Am Chem Soc. 2014 Sep 24;136(38):13102-5Download PDF.

  5. Liu Y, Tan YL, Zhang X, Bhabha G, Ekiert DC, Genereux JC, Cho Y, Kipnis Y, Bjelic S, Baker D, Kelly JW. Small molecule probes to quantify the functional fraction of a specific protein in a cell with minimal folding equilibrium shifts.
    Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4449-54Download PDF.

  6. Friesen RH, Lee PS, Stoop EJ, Hoffman RM, Ekiert DC, Bhabha G, Yu W, Juraszek J, Koudstaal W, Jongeneelen M, Korse HJ, Ophorst C, Brinkman-van der Linden EC, Throsby M, Kwakkenbos MJ, Bakker AQ, Beaumont T, Spits H, Kwaks T, Vogels R, Ward AB, Goudsmit J, Wilson IA. A common solution to group 2 influenza virus neutralization.
    Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):445-50Download PDF.

  7. Bhabha G, Ekiert DC, Jennewein M, Zmasek CM, Tuttle LM, Kroon G, Dyson HJ, Godzik A, Wilson IA, Wright PE. Divergent evolution of protein conformational dynamics in dihydrofolate reductase.
    Nat Struct Mol Biol. 2013 Nov;20(11):1243-9Download PDF.

  8. Wang F*, Ekiert DC*, Ahmad I, Yu W, Zhang Y, Bazirgan O, Torkamani A, Raudsepp T, Mwangi W, Criscitiello MF, Wilson IA, Schultz PG, Smider VV. Reshaping antibody diversity.
    Cell. 2013 Jun 6;153(6):1379-93Download PDF.

  9. Dreyfus C, Ekiert DC, Wilson IA. Structure of a classical broadly neutralizing stem antibody in complex with a pandemic H2 influenza virus hemagglutinin.
    J Virol. 2013 Jun;87(12):7149-54Download PDF.

  10. Tsibane T*, Ekiert DC*, Krause JC*, Martinez O, Crowe JE Jr, Wilson IA, Basler CF. Influenza human monoclonal antibody 1F1 interacts with three major antigenic sites and residues mediating human receptor specificity in H1N1 viruses.
    PLoS Pathog. 2012;8(12):e1003067Download PDF.

  11. Lee PS, Yoshida R, Ekiert DC, Sakai N, Suzuki Y, Takada A, Wilson IA. Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity.
    Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):17040-5Download PDF.

  12. Ekiert DC*, Kashyap AK*, Steel J, Rubrum A, Bhabha G, Khayat R, Lee JH, Dillon MA, O'Neil RE, Faynboym AM, Horowitz M, Horowitz L, Ward AB, Palese P, Webby R, Lerner RA, Bhatt RR, Wilson IA. Cross-neutralization of influenza A viruses mediated by a single antibody loop.
    Nature. 2012 Sep 27;489(7417):526-32Download PDF.

  13. Buck-Koehntop BA, Stanfield RL, Ekiert DC, Martinez-Yamout MA, Dyson HJ, Wilson IA, Wright PE. Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso.
    Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15229-34Download PDF.

  14. Schneemann A, Speir JA, Tan GS, Khayat R, Ekiert DC, Matsuoka Y, Wilson IA. A virus-like particle that elicits cross-reactive antibodies to the conserved stem of influenza virus hemagglutinin.
    J Virol. 2012 Nov;86(21):11686-97Download PDF.

  15. Dreyfus C, Laursen NS, Kwaks T, Zuijdgeest D, Khayat R, Ekiert DC, Lee JH, Metlagel Z, Bujny MV, Jongeneelen M, van der Vlugt R, Lamrani M, Korse HJ, Geelen E, Sahin Ö, Sieuwerts M, Brakenhoff JP, Vogels R, Li OT, Poon LL, Peiris M, Koudstaal W, Ward AB, Wilson IA, Goudsmit J, Friesen RH. Highly conserved protective epitopes on influenza B viruses.
    Science. 2012 Sep 14;337(6100):1343-8Download PDF.

  16. Nycholat CM, McBride R, Ekiert DC, Xu R, Rangarajan J, Peng W, Razi N, Gilbert M, Wakarchuk W, Wilson IA, Paulson JC. Recognition of sialylated poly-N-acetyllactosamine chains on N- and O-linked glycans by human and avian influenza A virus hemagglutinins.
    Angew Chem Int Ed Engl. 2012 May 14;51(20):4860-3Download PDF.

  17. Ekiert DC, Wilson IA. Broadly neutralizing antibodies against influenza virus and prospects for universal therapies.
    Curr Opin Virol. 2012 Apr;2(2):134-41Download PDF.

  18. Ekiert DC*, Friesen RH*, Bhabha G, Kwaks T, Jongeneelen M, Yu W, Ophorst C, Cox F, Korse HJ, Brandenburg B, Vogels R, Brakenhoff JP, Kompier R, Koldijk MH, Cornelissen LA, Poon LL, Peiris M, Koudstaal W, Wilson IA, Goudsmit J. A highly conserved neutralizing epitope on group 2 influenza A viruses.
    Science. 2011 Aug 12;333(6044):843-50Download PDF.

  19. Fleishman SJ*, Whitehead TA*, Ekiert DC*, Dreyfus C, Corn JE, Strauch EM, Wilson IA, Baker D. Computational design of proteins targeting the conserved stem region of influenza hemagglutinin.
    Science. 2011 May 13;332(6031):816-21Download PDF.

  20. Bhabha G, Lee J, Ekiert DC, Gam J, Wilson IA, Dyson HJ, Benkovic SJ, Wright PE. A dynamic knockout reveals that conformational fluctuations influence the chemical step of enzyme catalysis.
    Science. 2011 Apr 8;332(6026):234-8Download PDF.

  21. Krause JC*, Ekiert DC*, Tumpey TM, Smith PB, Wilson IA, Crowe JE Jr. An insertion mutation that distorts antibody binding site architecture enhances function of a human antibody.
    MBio. 2011 Feb 8;2(1):e00345-10Download PDF.

  22. Wang TT, Tan GS, Hai R, Pica N, Ngai L, Ekiert DC, Wilson IA, García-Sastre A, Moran TM, Palese P. Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes.
    Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18979-84Download PDF.

  23. Xu R*, Ekiert DC*, Krause JC, Hai R, Crowe JE Jr, Wilson IA. Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus.
    Science. 2010 Apr 16;328(5976):357-60Download PDF.

  24. Ekiert DC, Bhabha G, Elsliger MA, Friesen RH, Jongeneelen M, Throsby M, Goudsmit J, Wilson IA. Antibody recognition of a highly conserved influenza virus epitope.
    Science. 2009 Apr 10;324(5924):246-51Download PDF.

  25. Simon GC, Schonteich E, Wu CC, Piekny A, Ekiert D, Yu X, Gould GW, Glotzer M, Prekeris R. Sequential Cyk-4 binding to ECT2 and FIP3 regulates cleavage furrow ingression and abscission during cytokinesis.
    EMBO J. 2008 Jul 9;27(13):1791-803Download PDF.

  26. Matic I, Ekiert D, Radman M, Kohiyama M. Generation of DNA-free Escherichia coli cells by 2-aminopurine requires mismatch repair and nonmethylated DNA.
    J Bacteriol. 2006 Jan;188(1):339-42Download PDF.

  27. Strauss B, Kelly K, Ekiert D. Cytochrome oxidase deficiency protects Escherichia coli from cell death but not from filamentation due to thymine deficiency or DNA polymerase inactivation.
    J Bacteriol. 2005 Apr;187(8):2827-35Download PDF.

  28. Strauss B, Kelly K, Dincman T, Ekiert D, Biesieda T, Song R. Cell death in Escherichia coli dnaE(Ts) mutants incubated at a nonpermissive temperature is prevented by mutation in the cydA gene.
    J Bacteriol. 2004 Apr;186(7):2147-55Download PDF.