The principal objective is to compare the three-dimensional structures, at atomic resolution, of strains and mutants of rhino (common cold) viruses as well as other picornaviruses (particularly Mengo virus) in order to determine how their functions are controlled by their chemical structures. In light of the known sequence homologies among picornaviruses, these studies should also provide considerable understanding of the structure-function relationship of poliovirus (PV) and of foot-and-mouth disease virus (FMDV). Slight modifications of the structures of these viruses must determine tissue and host specificity as well as differing immune responses. The primary tool is single crystal X-ray crystallography. An exceptionally beautiful 3.5 angstroms resolution electron density map of human rhinovirus 14 (HRV14) was computed during the time that this proposal was being prepared. This is the first atomic resolution structure of an animal virus. The map was fully interpreted with respect to the known amino acid sequences of the four structural proteins (there are 60 copies of each in a virion) within three days. The quality of the map derives from the use of the icosahedral symmetry to determine phases and the high quality of the data collected at the Cornell synchrotron (CHESS). We have 2.6 angstroms resolution native data collected and processed, and plan to refine the structure to this resolution. The novel methods we have used open up the possibility of rapid structure determination of many other icosahedral viruses. The electron density map confirmed the surface position of the previously identified antigenic sites of HRV, PV and FMDV. It was also possible to associate a large surface cavity with the host cell receptor recognition site. Conformational changes appear to accompany neutralization of picornaviruses by antibody binding. Furthermore, there are multiple serotypes of rhinoviruses compared to only 3 serotypes of polio and 7 of FMDV. The large number of HRV serotypes is the underlying problem in the development of a viable common cold vaccine. These problems are to be investigated by studying monoclonal antibodies (or their Fab fragments) complexed with HRV14. Complexes of antibody with antigenic peptides of neutralizing epitopes are also to be crystallized and analyzed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI011219-18
Application #
3480589
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1976-04-01
Project End
1991-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
18
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Purdue University
Department
Type
Schools of Arts and Sciences
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
De Castro, Cristina; Klose, Thomas; Speciale, Immacolata et al. (2018) Structure of the chlorovirus PBCV-1 major capsid glycoprotein determined by combining crystallographic and carbohydrate molecular modeling approaches. Proc Natl Acad Sci U S A 115:E44-E52
Zhu, Dongjie; Wang, Xiangxi; Fang, Qianglin et al. (2018) Pushing the resolution limit by correcting the Ewald sphere effect in single-particle Cryo-EM reconstructions. Nat Commun 9:1552
Baggen, Jim; Thibaut, Hendrik Jan; Staring, Jacqueline et al. (2016) Enterovirus D68 receptor requirements unveiled by haploid genetics. Proc Natl Acad Sci U S A 113:1399-404
Liu, Yue; Hill, Marchel G; Klose, Thomas et al. (2016) Atomic structure of a rhinovirus C, a virus species linked to severe childhood asthma. Proc Natl Acad Sci U S A 113:8997-9002
Klose, Thomas; Reteno, Dorine G; Benamar, Samia et al. (2016) Structure of faustovirus, a large dsDNA virus. Proc Natl Acad Sci U S A 113:6206-11
Liu, Yue; Sheng, Ju; Baggen, Jim et al. (2015) Sialic acid-dependent cell entry of human enterovirus D68. Nat Commun 6:8865
Klose, Thomas; Herbst, Dominik A; Zhu, Hanyu et al. (2015) A Mimivirus Enzyme that Participates in Viral Entry. Structure 23:1058-65
Liu, Yue; Sheng, Ju; Fokine, Andrei et al. (2015) Structure and inhibition of EV-D68, a virus that causes respiratory illness in children. Science 347:71-4
Reteno, Dorine Gaƫlle; Benamar, Samia; Khalil, Jacques Bou et al. (2015) Faustovirus, an asfarvirus-related new lineage of giant viruses infecting amoebae. J Virol 89:6585-94
Rossmann, Michael G (2014) Serial crystallography using synchrotron radiation. IUCrJ 1:84-6

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