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| Subject Categories: Microbiology & Pathogens | Structural Biology |
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| The EMBO Journal
(2005) 24, 4144–4153, doi:10.1038/sj.emboj.7600875 Published online 17 November 2005 |
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| Structure of unliganded HSV gD reveals a mechanism for receptor-mediated activation of virus entry |
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| Claude Krummenacher1, Vinit M Supekar2, J Charles Whitbeck3, Eric Lazear1, Sarah A Connolly1, Roselyn J Eisenberg3, Gary H Cohen1, Don C Wiley4, 5 and Andrea Carfí2 |
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1 Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA 2 Biochemistry Department, IRBM P Angeletti, Pomezia, Rome, Italy 3 Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA 4 Children's Hospital Laboratory of Molecular Medicine, Boston, MA, USA To whom correspondence should be addressed Andrea Carfí, Department of Biochemistry, IRBM P Angeletti, Via Pontina Km 30,600, 10040 Pomezia, Rome, Italy. Tel.: +39 06 9109 3550; Fax: +39 06 9109 3225; E-mail: andrea_carfi@merck.com 5 Deceased Received 25 August 2005; Accepted 25 October 2005; Published online 17 November 2005. |
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| Abstract |
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| Herpes simplex virus (HSV) entry into cells requires binding of the envelope glycoprotein D (gD) to one of several cell surface receptors. The 50 C-terminal residues of the gD ectodomain are essential for virus entry, but not for receptor binding. We have determined the structure of an unliganded gD molecule that includes these C-terminal residues. The structure reveals that the C-terminus is anchored near the N-terminal region and masks receptor-binding sites. Locking the C-terminus in the position observed in the crystals by an intramolecular disulfide bond abolished receptor binding and virus entry, demonstrating that this region of gD moves upon receptor binding. Similarly, a point mutant that would destabilize the C-terminus structure was nonfunctional for entry, despite increased affinity for receptors. We propose that a controlled displacement of the gD C-terminus upon receptor binding is an essential feature of HSV entry, ensuring the timely activation of membrane fusion. |
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| Keywords: glycoprotein D, herpes simplex virus, receptor binding, viral entry |
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