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research advances

January 2013 research highlights

PSI Impact: More “Ex-cited” Use of PSI structures

SBKB [doi:10.1038/sbkb.2012.121]

This highlight is the second half of a series on the use of Google Scholar to find unpublished PSI protein structures that still made an impact on structural biology research.

  • (A) The alpha-carbon backbone of the human Toll-like receptor/Interleukin-1 receptor domain of MyD (PDB 2JS7) is colored from the N-terminus (blue) to the C-terminus (red). (B) The long-chain-fatty-acid-CoA ligase (FadD1) from Archaeoglobus fulgidus (PDB 3G7S). Like other LC-FACLs, FadD1 biologically assembles into a dimer (each monomer shown in green a

Since 2001, the Protein Structure Initiative has solved more than 6,000 structures in a high-throughput (HTP) mode. While those structures are available in the Protein Data Bank within four weeks of refinement completion, to date only 22% have primary citations. Nonetheless, many structures are still being found by the community and used in further analyses.

Last month, examples from the HTP centers PSI JCSG and PSI MCSG were described. This month, we present examples from PSI NESG and PSI NYSGRC.

PSI NESG

In 2007, the NESG determined the solution NMR structure of the Toll-like receptor/interleukin-1 receptor domain of myeloid differentiation primary response protein (MyD88-TIR; PDB 2JS7). Toll-like receptors (TLRs) play a key role in the innate immune system. MyD88 is a 296-amino acid protein that mediates signal transduction from activated TLRs to downstream components in the innate immune response pathway; mutations of MyD88 are associated with human lymphomas. MyD88 was selected as part of the NESG Biomedical Theme project on protein interaction networks associated with cancer biology. 1 The NESG determined the TIR domain, spanning MyD88 residues 145–296, by solution NMR methods. The TIR domain structure is comprised of a three-layer αβ sandwich architecture belonging to the Rossmann fold CATH topology family (a five-stranded parallel β-sheet flanked on two sides by α-helices).

The NESG MyD88-TlR structure was the first structural representative of its class (GO:0045351). Since the release of its coordinates, 2JS7 has been cited in 13 publications, which in turn were cited by an additional 233 publications. Key publications citing 2JS7 are described below.

Structurally guided point mutations were introduced into MyD88-TIR, followed by cell-based assays that resulted in the identification of three discrete surface sites in the TIR domain important for TLR4 signaling.

  • Ohnishi, H. , et al.. Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling. Proc Natl Acad Sci USA. 106, 10260–10265 (2009). (cited 45 times)

Comparisons of human MyD88-TIR domain structures (including 2JS7) and bacterial and viral TIR domain structures reveal a number of microbial homologues of the TIR domain suggest potential interference mechanisms through mimicry of host proteins.

  • Xiao, T.S. Subversion of innate immune signaling through molecular mimicry. J Clin Immunol. 30, 638–642. (2010) (cited 7 times)

2JS7 and 17 other NESG NMR structures were included in a 40-structure training set to design a new chemical shift predictions algorithm.

  • Lehtivarjo, J. , et al. 4D prediction of protein (1)H chemical shifts. J Biomol NMR. 45, 413–426 (2009). (cited 14 times)

PSI NYSG(X)RC

The crystal structure of a long-chain-fatty-acid-CoA ligase (FadD1) from Archaeoglobus fulgidus (PDB 3G7S) was solved by the PSI NYSGXRC in early 2009. This protein is ubiquitously present in all organisms due to its role in the metabolism of complex fatty acid chains. The target was selected as part of a wider structural coverage project aimed at solving the structures of unrepresented sequence families, and thus providing templates for modeling studies. At the time of release, only one other homolog from Thermus thermophilus and an N-terminal region from the Mycobacterium tuberculosis homolog were available. Since then, this structure has been used and cited by many articles, listed below.

Sequence and structural comparison studies.

  • Lee, T.V. , et al. Structure of a eukaryotic nonribosomal peptide synthetase adenylation domain that activates a large hydroxamate amino acid in siderophore biosynthesis. J Biol Chem. 285(4), 2415–2427 (2010). (cited 10 times)
  • Gulick, A.M. Conformational Dynamics in the Acyl-CoA Synthetases, Adenylation Domains of Non-ribosomal Peptide Synthetases, and Firefly Luciferase. ACS Chem. Biol. 4(10), 811–827 (2009). (cited 9 times)

Used as a template for modeling of sequence homologs.

  • Kaur, J. et al. Bioinformatic Analysis of Leishmania donovani Long-Chain Fatty Acid-CoA Ligase as a Novel Drug Target. Mol Biol Int.278051 (2011). (cited 1 time)
  • Koetsier, M.J. et al. Aminoacyl-coenzyme A synthesis catalyzed by a CoA ligase from Penicillium chrysogenum. FEBS Lett. 585(6), 893–898 (2011). (cited 1 time)

Gaetano Montelione, Greg Kornhaber, Steven Almo, Jeffrey Bonanno & Maggie Gabanyi

 

References:

  1. Y.J. Huang et al. Targeting the human cancer pathway protein interaction network by structural genomics.
    Mol. Cell. Proteomics. 7, 2048-2060 (2008). doi:10.1074/mcp.M700550-MCP200

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