Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Structure of the Mediator head module


Gene transcription by RNA polymerase (Pol) II requires the coactivator complex Mediator. Mediator connects transcriptional regulators and Pol II, and is linked to human disease1,2,3,4. Mediator from the yeast Saccharomyces cerevisiae has a molecular mass of 1.4 megadaltons and comprises 25 subunits that form the head, middle, tail and kinase modules5,6,7. The head module constitutes one-half of the essential Mediator core8, and comprises the conserved9 subunits Med6, Med8, Med11, Med17, Med18, Med20 and Med22. Recent X-ray analysis of the S. cerevisiae head module at 4.3 Å resolution led to a partial architectural model with three submodules called neck, fixed jaw and moveable jaw10. Here we determine de novo the crystal structure of the head module from the fission yeast Schizosaccharomyces pombe at 3.4 Å resolution. Structure solution was enabled by new structures of Med6 and the fixed jaw, and previous structures of the moveable jaw11 and part of the neck12, and required deletion of Med20. The S. pombe head module resembles the head of a crocodile with eight distinct elements, of which at least four are mobile. The fixed jaw comprises tooth and nose domains, whereas the neck submodule contains a helical spine and one limb, with shoulder, arm and finger elements. The arm and the essential shoulder contact other parts of Mediator. The jaws and a central joint are implicated in interactions with Pol II and its carboxy-terminal domain, and the joint is required for transcription in vitro. The S. pombe head module structure leads to a revised model of the S. cerevisiae module, reveals a high conservation and flexibility, explains known mutations, and provides the basis for unravelling a central mechanism of gene regulation.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Structures of Med6 and Med17C–Med11C–Med22C.
Figure 2: Structure of Sp Mediator head module.
Figure 3: Structural elements and surface conservation.
Figure 4: Head module integrity and interactions.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

Atomic coordinate files and structure factorswere deposited in the Protein Data Bank under accession codes 4H61 (Sp Med6), 4H62 (Sc Med17C–Med11C–Med22C) and 4H63 (Sp head module). See Supplementary Data for the coordinate file for the revised Sc head module model.


  1. Conaway, R. C. & Conaway, J. W. Origins and activity of the Mediator complex. Semin. Cell Dev. Biol. 22, 729–734 (2011)

    CAS  Article  Google Scholar 

  2. Chen, W. & Roeder, R. G. Mediator-dependent nuclear receptor function. Semin. Cell Dev. Biol. (2011)

  3. Kaufmann, R. et al. Infantile cerebral and cerebellar atrophy is associated with a mutation in the MED17 subunit of the transcription preinitiation mediator complex. Am. J. Hum. Genet. 87, 667–670 (2010)

    CAS  Article  Google Scholar 

  4. Myers, L. C. et al. The Med proteins of yeast and their function through the RNA polymerase II carboxy-terminal domain. Genes Dev. 12, 45–54 (1998)

    CAS  Article  Google Scholar 

  5. Asturias, F. J., Jiang, Y. W., Myers, L. C., Gustafsson, C. M. & Kornberg, R. D. Conserved structures of mediator and RNA polymerase II holoenzyme. Science 283, 985–987 (1999)

    ADS  CAS  Article  Google Scholar 

  6. Kang, J. S. et al. The structural and functional organization of the yeast mediator complex. J. Biol. Chem. 276, 42003–42010 (2001)

    CAS  Article  Google Scholar 

  7. Davis, J. A., Takagi, Y., Kornberg, R. & Asturias, F. Structure of the yeast RNA polymerase II holoenzyme: mediator conformation and polymerase interaction. Mol. Cell 10, 409–415 (2002)

    CAS  Article  Google Scholar 

  8. Liu, Y., Ranish, J. A., Aebersold, R. & Hahn, S. Yeast nuclear extract contains two major forms of RNA polymerase II mediator complexes. J. Biol. Chem. 276, 7169–7175 (2001)

    CAS  Article  Google Scholar 

  9. Bourbon, H. M. Comparative genomics supports a deep evolutionary origin for the large, four-module transcriptional mediator complex. Nucleic Acids Res. 36, 3993–4008 (2008)

    CAS  Article  Google Scholar 

  10. Imasaki, T. et al. Architecture of the Mediator head module. Nature 475, 240–243 (2011)

    CAS  Article  Google Scholar 

  11. Larivière, L. et al. Structure and TBP binding of the Mediator head subcomplex Med8–Med18–Med20. Nature Struct. Mol. Biol. 13, 895–901 (2006)

    Article  Google Scholar 

  12. Seizl, M., Lariviere, L., Pfaffeneder, T., Wenzeck, L. & Cramer, P. Mediator head subcomplex Med11/22 contains a common helix bundle building block with a specific function in transcription initiation complex stabilization. Nucleic Acids Res. 39, 6291–6304 (2011)

    CAS  Article  Google Scholar 

  13. Larivière, L., Seizl, M. & Cramer, P. A structural perspective on Mediator function. Curr. Opin. Cell Biol. (2012)

  14. Larivière, L. et al. Structure-system correlation identifies a gene regulatory Mediator submodule. Genes Dev. 22, 872–877 (2008)

    Article  Google Scholar 

  15. Baumli, S., Hoeppner, S. & Cramer, P. A conserved mediator hinge revealed in the structure of the MED7·MED21 (Med7·Srb7) heterodimer. J. Biol. Chem. 280, 18171–18178 (2005)

    CAS  Article  Google Scholar 

  16. Guglielmi, B. et al. A high resolution protein interaction map of the yeast Mediator complex. Nucleic Acids Res. 32, 5379–5391 (2004)

    CAS  Article  Google Scholar 

  17. Cai, G. et al. Mediator head module structure and functional interactions. Nature Struct. Mol. Biol. 17, 273–279 (2010)

    CAS  Article  Google Scholar 

  18. Takagi, Y. & Kornberg, R. D. Mediator as a general transcription factor. J. Biol. Chem. 281, 80–89 (2006)

    CAS  Article  Google Scholar 

  19. Esnault, C. et al. Mediator-dependent recruitment of TFIIH modules in preinitiation complex. Mol. Cell 31, 337–346 (2008)

    CAS  Article  Google Scholar 

  20. Lee, Y. C. & Kim, Y. J. Requirement for a functional interaction between mediator components Med6 and Srb4 in RNA polymerase II transcription. Mol. Cell. Biol. 18, 5364–5370 (1998)

    CAS  Article  Google Scholar 

  21. Lee, T. I. et al. Interplay of positive and negative regulators in transcription initiation by RNA polymerase II holoenzyme. Mol. Cell. Biol. 18, 4455–4462 (1998)

    CAS  Article  Google Scholar 

  22. Soutourina, J., Wydau, S., Ambroise, Y., Boschiero, C. & Werner, M. Direct interaction of RNA polymerase II and mediator required for transcription in vivo . Science 331, 1451–1454 (2011)

    ADS  CAS  Article  Google Scholar 

  23. Tan, Q., Linask, K. L., Ebright, R. H. & Woychik, N. A. Activation mutants in yeast RNA polymerase II subunit RPB3 provide evidence for a structurally conserved surface required for activation in eukaryotes and bacteria. Genes Dev. 14, 339–348 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Thompson, C. M., Koleske, A. J., Chao, D. M. & Young, R. A. A multisubunit complex associated with the RNA polymerase II CTD and TATA-binding protein in yeast. Cell 73, 1361–1375 (1993)

    CAS  Article  Google Scholar 

  25. Näär, A. M., Taatjes, D. J., Zhai, W., Nogales, E. & Tjian, R. Human CRSP interacts with RNA polymerase II CTD and adopts a specific CTD-bound conformation. Genes Dev. 16, 1339–1344 (2002)

    Article  Google Scholar 

  26. Nonet, M. L. & Young, R. A. Intragenic and extragenic suppressors of mutations in the heptapeptide repeat domain of Saccharomyces cerevisiae RNA polymerase II. Genetics 123, 715–724 (1989)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Koleske, A. J., Buratowski, S., Nonet, M. & Young, R. A. A novel transcription factor reveals a functional link between the RNA polymerase II CTD and TFIID. Cell 69, 883–894 (1992)

    CAS  Article  Google Scholar 

  28. Takagi, Y. et al. Head module control of mediator interactions. Mol. Cell 23, 355–364 (2006)

    CAS  Article  Google Scholar 

  29. Baek, H. J., Kang, Y. K. & Roeder, R. G. Human Mediator enhances basal transcription by facilitating recruitment of transcription factor IIB during preinitiation complex assembly. J. Biol. Chem. 281, 15172–15181 (2006)

    CAS  Article  Google Scholar 

  30. Ranish, J. A., Yudkovsky, N. & Hahn, S. Intermediates in formation and activity of the RNA polymerase II preinitiation complex: holoenzyme recruitment and a postrecruitment role for the TATA box and TFIIB. Genes Dev. 13, 49–63 (1999)

    CAS  Article  Google Scholar 

  31. Edgar, R. C. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32, 1792–1797 (2004)

    CAS  Article  Google Scholar 

  32. Gouet, P., Courcelle, E., Stuart, D. I. & Metoz, F. ESPript: analysis of multiple sequence alignments in PostScript. Bioinformatics 15, 305–308 (1999)

    CAS  Article  Google Scholar 

  33. Budisa, N. et al. High-level biosynthetic substitution of methionine in proteins by its analogs 2-aminohexanoic acid, selenomethionine, telluromethionine and ethionine in Escherichia coli . Eu. J. Biochem. 230, 788–796 (1995)

    CAS  Article  Google Scholar 

  34. Kabsch, W. Xds. Acta Crystallogr. D 66, 125–132 (2010)

    CAS  Article  Google Scholar 

  35. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010)

    CAS  Article  Google Scholar 

  36. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010)

    CAS  Article  Google Scholar 

  37. Karplus, P. A. & Diederichs, K. Linking crystallographic model and data quality. Science 336, 1030–1033 (2012)

    ADS  CAS  Article  Google Scholar 

  38. Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12–21 (2010)

    CAS  Article  Google Scholar 

  39. Sheldrick, G. M. A short history of SHELX. Acta Crystallogr. A 64, 112–122 (2008)

    ADS  CAS  Article  Google Scholar 

  40. Seizl, M. et al. A conserved GA element in TATA-less RNA polymerase II promoters. PLoS ONE 6, e27595 (2011)

    ADS  CAS  Article  Google Scholar 

  41. Schneider, G. & Lindqvist, Y. Ta6Br14 is a useful cluster compound for isomorphous replacement in protein crystallography. Acta Crystallogr. D 50, 186–191 (1994)

    CAS  Article  Google Scholar 

  42. Knäblein, J. et al. Ta6Br12 2+, a tool for phase determination of large biological assemblies by X-ray crystallography. J. Mol. Biol. 270, 1–7 (1997)

    ADS  Article  Google Scholar 

  43. Cramer, P. et al. Architecture of RNA polymerase II and implications for the transcription mechanism. Science 288, 640–649 (2000)

    ADS  CAS  Article  Google Scholar 

  44. Girard, E., Stelter, M., Vicat, J. & Kahn, R. A new class of lanthanide complexes to obtain high-phasing-power heavy-atom derivatives for macromolecular crystallography. Acta Crystallogr. D 59, 1914–1922 (2003)

    Article  Google Scholar 

  45. Vonrhein, C., Blanc, E., Roversi, P. & Bricogne, G. Automated structure solution with autoSHARP. Methods Mol. Biol. 364, 215–230 (2007)

    CAS  Google Scholar 

  46. Terwilliger, T. C. Maximum-likelihood density modification. Acta Crystallogr. D 56, 965–972 (2000)

    CAS  Article  Google Scholar 

  47. Blanc, E. et al. Refinement of severely incomplete structures with maximum likelihood in BUSTER-TNT. Acta Crystallogr. D Biol 60, 2210–2221 (2004)

    CAS  Article  Google Scholar 

  48. Eswar, N. et al. Comparative protein structure modeling using MODELLER. Curr. Protoc. Bioinformatics Chapter 5, 5.6.1 (2006)

    Article  Google Scholar 

Download references


We thank S. Baumli, A. C. Cheung, A. Imhof and C. Schmidt for help. We acknowledge the crystallization facility at the Max Planck Institute of Biochemistry, Martinsried. Diffraction data were collected at the Swiss Light Source, Villigen, Switzerland. M.S. was supported by a Boehringer Ingelheim fellowship and the Elite Network of Bavaria. P.C. was supported by the Deutsche Forschungsgemeinschaft, SFB646, TR5, GraKo1721, SFB960, CIPSM, NIM, an Advanced Grant of the European Research Council, the LMUinnovativ project Bioimaging Network, the Vallee Foundation, and the Jung-Stiftung.

Author information

Authors and Affiliations



L.L. designed crystallization constructs, established expression and purification strategies for head modules, solved the Med6 and Med17C–Med11C–Med22C structures, carried out crystallographic data analysis for Sp head module structure determination, built the Sc head module model, generated yeast strains, and performed in vivo studies. C.P. optimized Sp head module purification, purified and crystallized the Sp head module variants, and prepared heavy metal derivatives. L.L. and C.P. collected diffraction data for the head module and carried out model building and structural analysis. M.S. contributed to establishing expression and purification strategies and carried out transcription assays. L.W. provided technical help. F.K. optimized transcription assays. P.C. initiated and supervised the project. P.C., L.L., C.P. and M.S. prepared the manuscript.

Corresponding authors

Correspondence to Laurent Larivière or Patrick Cramer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Notes 1-2, Supplementary Figures 1-12, Supplementary Tables 1-3 and Supplementary References. (PDF 10571 kb)

Supplementary Data

This file contains the coordinates in PDB format for the revised Sc Mediator head module model. Subunits Med6, Med8, Med11, Med17, Med18, Med20 and Med22 correspond to chains F, H, K, Q, R, T and V, respectively. This file was originally missing and was added online on 19 December 2012. (TXT 457 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Larivière, L., Plaschka, C., Seizl, M. et al. Structure of the Mediator head module. Nature 492, 448–451 (2012).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing