Giuseppe
Emeritus
[Source: Proceedings of the National Academy of Sciences of the United States of America, full text: (LINK). Abstract, edited.]
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Structure of human enterovirus 71 in complex with a capsid-binding inhibitor
Pavel Plevka<SUP>a</SUP>,<SUP>1</SUP>, Rushika Perera<SUP>a</SUP>,<SUP>1</SUP>, Moh Lan Yap<SUP>a</SUP>, Jane Cardosa<SUP>b</SUP>, Richard J. Kuhn<SUP>a</SUP>, and Michael G. Rossmann<SUP>a</SUP>,<SUP>2</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Department of Biological Sciences, Purdue University, West Lafayette, IN 47907-2032; and <SUP>b</SUP>Sentinext Therapeutics, 10050 Penang, Malaysia
Edited by Robert A. Lamb, Northwestern University, Evanston, IL, and approved February 22, 2013 (received for review December 21, 2012)
Abstract
Human enterovirus 71 is a picornavirus causing hand, foot, and mouth disease that may progress to fatal encephalitis in infants and small children. As of now, no cure is available for enterovirus 71 infections. Small molecule inhibitors binding into a hydrophobic pocket within capsid viral protein 1 were previously shown to effectively limit infectivity of many picornaviruses. Here we report a 3.2-?-resolution X-ray structure of the enterovirus 71 virion complexed with the capsid-binding inhibitor WIN 51711. The inhibitor replaced the natural pocket factor within the viral protein 1 pocket without inducing any detectable rearrangements in the structure of the capsid. Furthermore, we show that the compound stabilizes enterovirus 71 virions and limits its infectivity, probably through restricting dynamics of the capsid necessary for genome release. Thus, our results provide a structural basis for development of antienterovirus 71 capsid-binding drugs.
stability ? virus
Footnotes
<SUP>1</SUP>R.P. and P.P. contributed equally to this work.
<SUP>2</SUP>To whom correspondence should be addressed. E-mail: mr@purdue.edu.
Author contributions: P.P., R.P., R.J.K., and M.G.R. designed research; P.P., R.P., and M.L.Y. performed research; P.P. and R.P. analyzed data; J.C. contributed new reagents/analytic tools; and P.P., R.P., and M.G.R. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The EV71 native and inhibitor complex coordinates, observed structure amplitudes, and phases derived by the phase extension have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3ZFE, 3ZFF, and 3ZFG).
-Pavel Plevka<SUP>a</SUP>,<SUP>1</SUP>, Rushika Perera<SUP>a</SUP>,<SUP>1</SUP>, Moh Lan Yap<SUP>a</SUP>, Jane Cardosa<SUP>b</SUP>, Richard J. Kuhn<SUP>a</SUP>, and Michael G. Rossmann<SUP>a</SUP>,<SUP>2</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Department of Biological Sciences, Purdue University, West Lafayette, IN 47907-2032; and <SUP>b</SUP>Sentinext Therapeutics, 10050 Penang, Malaysia
Edited by Robert A. Lamb, Northwestern University, Evanston, IL, and approved February 22, 2013 (received for review December 21, 2012)
Abstract
Human enterovirus 71 is a picornavirus causing hand, foot, and mouth disease that may progress to fatal encephalitis in infants and small children. As of now, no cure is available for enterovirus 71 infections. Small molecule inhibitors binding into a hydrophobic pocket within capsid viral protein 1 were previously shown to effectively limit infectivity of many picornaviruses. Here we report a 3.2-?-resolution X-ray structure of the enterovirus 71 virion complexed with the capsid-binding inhibitor WIN 51711. The inhibitor replaced the natural pocket factor within the viral protein 1 pocket without inducing any detectable rearrangements in the structure of the capsid. Furthermore, we show that the compound stabilizes enterovirus 71 virions and limits its infectivity, probably through restricting dynamics of the capsid necessary for genome release. Thus, our results provide a structural basis for development of antienterovirus 71 capsid-binding drugs.
stability ? virus
Footnotes
<SUP>1</SUP>R.P. and P.P. contributed equally to this work.
<SUP>2</SUP>To whom correspondence should be addressed. E-mail: mr@purdue.edu.
Author contributions: P.P., R.P., R.J.K., and M.G.R. designed research; P.P., R.P., and M.L.Y. performed research; P.P. and R.P. analyzed data; J.C. contributed new reagents/analytic tools; and P.P., R.P., and M.G.R. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The EV71 native and inhibitor complex coordinates, observed structure amplitudes, and phases derived by the phase extension have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 3ZFE, 3ZFF, and 3ZFG).
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