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Satish K. Nair Assistant Professor of Biochemistry and Biophysics Ph.D. 1994 University of Pennsylvania X-ray crystallography, enzymology, DNA replication Satish K. Nair 430 RAL, Box B-4, MC-712 600 S. Mathews Urbana, IL 61801 217-333-2688 s-nair@life.uiuc.edu

Research in my laboratory seeks to combine structure biology, in particular X-ray crystallography, with biochemical and biophysical methodologies in order to elucidate the relationships between atomic structure and biological functions of macromolecules.

Innate immune signaling: the last decade has borne witness to a tremendous influx of research aimed at elucidating mechanisms of signaling within the invertebrate and vertebrate innate immune pathway, a highly conserved, and ancient system that is the first line of defense against infection and pathogenic invasion.

Downstream signaling in innate immunity: The extracellular recognition receptors have been the focus of research from dozens of laboratories all over the world, but biochemical studies of downstream signaling components have only recently been carried out. Complementary structural and biochemical studies can provide tremendous insights into the molecular aspects of signaling. Our crystal structure of the interleukin receptor associated kinase-4 (IRAK-4) intracellular domain shows fundamental differences in the structure of multi-protein innate immune signaling complexes between vertebrates and invertebrate. More recently, we have obtained crystals of the universal adaptor MyD88 that diffract to 3.5 Å. We are currently optimizing the diffraction limits of these crystals for further structural studies.

Invertebrate pattern recognition receptors: The receptors that sense the presence of pathogens and subsequently mediate the innate immune response have been the focus of intense studies. We have determined the high resolution (1.3 Å) structure of the invertebrate, soluble β-1,3-glucan recognition receptor (a pattern recognition component of defense against fungal invasions) and have carried out extensive mutational and thermodynamic/calorimetric studies to elucidate the mechanism for recognition by this receptor. We demonstrated that receptor specificity is dictated by affinity to only long-chained glucans, such as those found on fungal cell-surfaces.

Frameworks for the (re)-design of novel antibiotics: microbial antibiotic resistance has become a major global health menace. As pathogens continue to develop resistance to the existing arsenal of antibiotics, efforts towards the production of new and/or more effective compounds are of fundamental importance.

Lantibiotic cyclase: In collaboration with the van der Donk laboratory, we have recently determined the 2.2 Å crystal structure of the lantibiotic cyclase involved in nisin biosynthesis. Lantibiotics are a class of molecules that disrupt the cell wall of Gram-positive bacteria, and despite their existence since antiquity, there are no known instances of bacterial resistance. Our work represents the first structure of a lantibiotic biosynthetic protein and our combined structural/biochemical studies have paved a way towards the production of a new class of antibiotic molecules.

Teicoplanin acyltransferase: Teicoplanin is a glycopeptide antibiotic that is currently the focus of substantial investigational efforts, including clinical trials. The efficacy of teicoplanin is due to its improved efficacy and superior pharmacokinetic profile compared to antibiotics like vancomycin (the "antibiotic of last resort"). Previous studies have established these properties of teicoplanin are due to the addition of long chain fatty acyl groups onto a structural scaffold and that the addition of the acyl groups is mediated by a tailoring acyltransferase. We have determined the crystal structure of tecioplanin acyltransferase to a resolution of 3 Å and a binary complex with decanoyl-CoA to 3.3 Å. We show that this enzyme also uses vancomycin as a substrate and improves the efficacy of vancomycin against resistant bacterial strains.

DNA replication: We are collaborating with the laboratory of Prof. Isaac Cann (Animal Sciences/Microbiology) towards structural studies of components of the archaeal DNA replisome. We have determined the crystal structure of the archaeal single-stranded DNA binding protein, replication protein A (RPA), to 2.4 Å resolution and the Cann lab has carried out extensive biochemical and biophysical studies on this molecule guided by our structural data. Our structure shows that the archaeal RPA harbors many of the structural features of the eukaryotic homolog in a more compact polypeptide.