Lectins are well known, multifaceted carbohydrate binding proteins that specifically recognize diverse sugar structures and mediate a variety of biological processes such as cell-cell and host-pathogen interactions, serum glycoprotein turnover and innate immune responses. In 1998, our laboratory solved the first solution structure of a cyanobacterial-derived protein, cyanovirin (CV-N) that exhibited potent HIV- inactivating properties. The structure revealed a novel three-dimensional fold, distinct from any known lectin folds. Extensive biochemical and structural characterizations based on our initial results and primarily from our laboratory led to the categorization of the new structural CVNH family. We previously determined a substantial number of type I CVNH proteins and are now embarking on structure/function studies of type III CVNHs. Similar to our work with CVN, we now have determined the three-dimensional structure of Oscillatoria Agardhii Agglutinin (OAA), another cyanobacterial anti-HIV lectin that shares sequence similarity with eight other proteins, the new OAAH family. No structural, carbohydrate-binding or other functional data were available prior to our recent first structure and no data on any of the family members is available.

Public Health Relevance

Structures, carbohydrate binding and anti-viral activity of CVNH and OAAH family lectins The long-term goal of this proposal is to understand the molecular mechanisms and structural basis of oligosaccharide recognition and the mode of action of HIV-inactivating lectins. We aim to gain a comprehensive molecular understanding of several classes of antiviral lectins and continue with our vigorous program that focuses on elucidating the structural, biochemical, and thermodynamic properties of type III CVNH family members as well as members of the new OAAH family. Results from this work will provide avenues to exploit these lectins in the fight against AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM080642-08
Application #
8724513
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Marino, Pamela
Project Start
2007-09-20
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Matei, Elena; Gronenborn, Angela M (2016) (19)F Paramagnetic Relaxation Enhancement: A Valuable Tool for Distance Measurements in Proteins. Angew Chem Int Ed Engl 55:150-4
Matei, Elena; Basu, Rohan; Furey, William et al. (2016) Structure and Glycan Binding of a New Cyanovirin-N Homolog. J Biol Chem 291:18967-76
Liu, Xinyu; Hillwig, Matthew L; Koharudin, Leonardus M I et al. (2016) Unified biogenesis of ambiguine, fischerindole, hapalindole and welwitindolinone: identification of a monogeranylated indolenine as a cryptic common biosynthetic intermediate by an unusual magnesium-dependent aromatic prenyltransferase. Chem Commun (Camb) 52:1737-40
Debiec, Karl T; Cerutti, David S; Baker, Lewis R et al. (2016) Further along the Road Less Traveled: AMBER ff15ipq, an Original Protein Force Field Built on a Self-Consistent Physical Model. J Chem Theory Comput 12:3926-47
Koharudin, Leonardus M I; Debiec, Karl T; Gronenborn, Angela M (2015) Structural Insight into Fungal Cell Wall Recognition by a CVNH Protein with a Single LysM Domain. Structure 23:2143-54
Carneiro, Marta G; Koharudin, Leonardus M I; Ban, David et al. (2015) Sampling of Glycan-Bound Conformers by the Anti-HIV Lectin Oscillatoria agardhii agglutinin in the Absence of Sugar. Angew Chem Int Ed Engl 54:6462-5
Carneiro, Marta G; Koharudin, Leonardus M I; Griesinger, Christian et al. (2015) (1)H, (13)C and (15)N resonance assignment of the anti-HIV lectin from Oscillatoria agardhii. Biomol NMR Assign 9:317-9
Férir, Geoffrey; Huskens, Dana; Noppen, Sam et al. (2014) Broad anti-HIV activity of the Oscillatoria agardhii agglutinin homologue lectin family. J Antimicrob Chemother 69:2746-58
Koharudin, Leonardus M I; Gronenborn, Angela M (2014) Antiviral lectins as potential HIV microbicides. Curr Opin Virol 7:95-100
Matei, Elena; André, Sabine; Glinschert, Anja et al. (2013) Fluorinated carbohydrates as lectin ligands: dissecting glycan-cyanovirin interactions by using 19F NMR spectroscopy. Chemistry 19:5364-74

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