PDBsum entry 2c3a

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protein ligands metals Protein-protein interface(s) links
Viral protein PDB id
Jmol PyMol
Protein chains
253 a.a. *
274 a.a. *
_ZN ×5
_CL ×2
_NA ×2
Waters ×53
* Residue conservation analysis
PDB id:
Name: Viral protein
Title: Structure of unliganded hsv gd reveals a mechanism for receptor-mediated activation of virus entry
Structure: Glycoprotein d. Chain: a, b. Engineered: yes. Mutation: yes. Other_details: n-acetyl-d-glucosamine linked to asn94 for both chains a and b
Source: Human herpesvirus 1. Human herpes simplex virus 1. Organism_taxid: 10298. Strain: patton. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
2.50Å     R-factor:   0.228     R-free:   0.275
Authors: C.Krummenacher,V.M.Supekar,J.C.Whitbeck,E.Lazear, S.A.Connolly,R.J.Eisenberg,G.H.Cohen,D.C.Wiley,A.Carfi
Key ref:
C.Krummenacher et al. (2005). Structure of unliganded HSV gD reveals a mechanism for receptor-mediated activation of virus entry. EMBO J, 24, 4144-4153. PubMed id: 16292345 DOI: 10.1038/sj.emboj.7600875
05-Oct-05     Release date:   21-Dec-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P57083  (GD_HHV1P) -  Envelope glycoprotein D
394 a.a.
253 a.a.*
Protein chain
Pfam   ArchSchema ?
P57083  (GD_HHV1P) -  Envelope glycoprotein D
394 a.a.
274 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     integral to membrane   1 term 


DOI no: 10.1038/sj.emboj.7600875 EMBO J 24:4144-4153 (2005)
PubMed id: 16292345  
Structure of unliganded HSV gD reveals a mechanism for receptor-mediated activation of virus entry.
C.Krummenacher, V.M.Supekar, J.C.Whitbeck, E.Lazear, S.A.Connolly, R.J.Eisenberg, G.H.Cohen, D.C.Wiley, A.Carfí.
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.
  Selected figure(s)  
Figure 1.
Figure 1 gD(23-306)[307C] structure. (A) Schematic representation of HSV-1 gD. Disulfide bonds are shown as black lines and N-linked oligosaccharides as lollipops. Colors of the N-terminal region, forming the HVEM-binding hairpin in the gD285-HVEM complex, the Ig-like core, and the C-terminal region past residue 255 are represented in green, yellow, and red, respectively. Positions of important amino acids and domain boundaries are numbered according to the mature form of gD. TM: transmembrane region. (B) Ribbon representation of the gD(23-306)[307C] subunit. The secondary structure elements are labeled as in Carfi et al (2001). The color code used is same as in (A). (C) As in (B) after 180 rotation as indicated. (D) Front view of gD(23-306)[307C] structure. The model is rotated 90 clockwise with respect to panel B to show the front side of gD, where the N- and C-terminal regions interact. (E) Front view of gD285 from the gD285-HVEM complex, with HVEM removed for clarity. (F) Front view of gD285 in the unbound state.
Figure 6.
Figure 6 Proposed mechanism for receptor-mediated activation of HSV gD. Envelope gD is shown, as a putative dimer, in its unbound state as well as during interaction with HVEM (top) or nectin-1 (bottom). Conformational changes are chronologically indicated by numbered arrows: (1) displacement of the C-terminus, (2) folding of the gD N-terminus in the case of HVEM binding, and (3) exposure of the PFD. The N-terminus of gD is shown in green, the C-terminus (290-299) is colored red, and the PFD (260-285) is pink.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: EMBO J (2005, 24, 4144-4153) copyright 2005.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21478902 S.A.Connolly, J.O.Jackson, T.S.Jardetzky, and R.Longnecker (2011).
Fusing structure and function: a structural view of the herpesvirus entry machinery.
  Nat Rev Microbiol, 9, 369-381.  
20130048 D.Atanasiu, J.C.Whitbeck, Leon, H.Lou, B.P.Hannah, G.H.Cohen, and R.J.Eisenberg (2010).
Bimolecular complementation defines functional regions of Herpes simplex virus gB that are involved with gH/gL as a necessary step leading to cell fusion.
  J Virol, 84, 3825-3834.  
19812609 I.A.Ho, L.Miao, K.C.Sia, G.Y.Wang, K.M.Hui, and P.Y.Lam (2010).
Targeting human glioma cells using HSV-1 amplicon peptide display vector.
  Gene Ther, 17, 250-260.  
20007280 J.O.Jackson, E.Lin, P.G.Spear, and R.Longnecker (2010).
Insertion mutations in herpes simplex virus 1 glycoprotein H reduce cell surface expression, slow the rate of cell fusion, or abrogate functions in cell fusion and viral entry.
  J Virol, 84, 2038-2046.  
20089288 K.M.Stiles, and C.Krummenacher (2010).
Glycoprotein D actively induces rapid internalization of two nectin-1 isoforms during herpes simplex virus entry.
  Virology, 399, 109-119.  
20573830 Q.Fan, and R.Longnecker (2010).
The Ig-like v-type domain of paired Ig-like type 2 receptor alpha is critical for herpes simplex virus type 1-mediated membrane fusion.
  J Virol, 84, 8664-8672.  
20147407 S.J.Dollery, M.G.Delboy, and A.V.Nicola (2010).
Low pH-induced conformational change in herpes simplex virus glycoprotein B.
  J Virol, 84, 3759-3766.  
20147400 T.Gianni, A.Cerretani, R.Dubois, S.Salvioli, S.S.Blystone, F.Rey, and G.Campadelli-Fiume (2010).
Herpes simplex virus glycoproteins H/L bind to cells independently of {alpha}V{beta}3 integrin and inhibit virus entry, and their constitutive expression restricts infection.
  J Virol, 84, 4013-4025.  
19217393 A.N.Kirschner, J.Sorem, R.Longnecker, and T.S.Jardetzky (2009).
Structure of Epstein-Barr virus glycoprotein 42 suggests a mechanism for triggering receptor-activated virus entry.
  Structure, 17, 223-233.
PDB code: 3fd4
19759132 C.C.Wright, T.W.Wisner, B.P.Hannah, R.J.Eisenberg, G.H.Cohen, and D.C.Johnson (2009).
Fusion between perinuclear virions and the outer nuclear membrane requires the fusogenic activity of herpes simplex virus gB.
  J Virol, 83, 11847-11856.  
19656900 E.Avitabile, C.Forghieri, and G.Campadelli-Fiume (2009).
Cross talk among the glycoproteins involved in herpes simplex virus entry and fusion: the interaction between gB and gH/gL does not necessarily require gD.
  J Virol, 83, 10752-10760.  
19217384 E.E.Heldwein (2009).
Entry of herpesviruses into cells: more than one way to pull the trigger.
  Structure, 17, 147-149.  
19129446 H.Uchida, W.A.Shah, A.Ozuer, A.R.Frampton, W.F.Goins, P.Grandi, J.B.Cohen, and J.C.Glorioso (2009).
Generation of herpesvirus entry mediator (HVEM)-restricted herpes simplex virus type 1 mutant viruses: resistance of HVEM-expressing cells and identification of mutations that rescue nectin-1 recognition.
  J Virol, 83, 2951-2961.  
19458262 L.Menotti, G.Nicoletti, V.Gatta, S.Croci, L.Landuzzi, C.De Giovanni, P.Nanni, P.L.Lollini, and G.Campadelli-Fiume (2009).
Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells.
  Proc Natl Acad Sci U S A, 106, 9039-9044.  
19196955 M.Backovic, R.Longnecker, and T.S.Jardetzky (2009).
Structure of a trimeric variant of the Epstein-Barr virus glycoprotein B.
  Proc Natl Acad Sci U S A, 106, 2880-2885.
PDB code: 3fvc
19457990 Q.Fan, E.Lin, T.Satoh, H.Arase, and P.G.Spear (2009).
Differential effects on cell fusion activity of mutations in herpes simplex virus 1 glycoprotein B (gB) dependent on whether a gD receptor or a gB receptor is overexpressed.
  J Virol, 83, 7384-7390.  
19104014 R.Akkarawongsa, N.E.Pocaro, G.Case, A.W.Kolb, and C.R.Brandt (2009).
Multiple peptides homologous to herpes simplex virus type 1 glycoprotein B inhibit viral infection.
  Antimicrob Agents Chemother, 53, 987-996.  
19805039 S.J.Kopp, G.Banisadr, K.Glajch, U.E.Maurer, K.Grünewald, R.J.Miller, P.Osten, and P.G.Spear (2009).
Infection of neurons and encephalitis after intracranial inoculation of herpes simplex virus requires the entry receptor nectin-1.
  Proc Natl Acad Sci U S A, 106, 17916-17920.  
19386594 T.Gianni, M.Amasio, and G.Campadelli-Fiume (2009).
Herpes simplex virus gD forms distinct complexes with fusion executors gB and gH/gL in part through the C-terminal profusion domain.
  J Biol Chem, 284, 17370-17382.  
18417564 B.Klupp, J.Altenschmidt, H.Granzow, W.Fuchs, and T.C.Mettenleiter (2008).
Glycoproteins required for entry are not necessary for egress of pseudorabies virus.
  J Virol, 82, 6299-6309.  
18715922 D.G.Meckes, and J.W.Wills (2008).
Structural rearrangement within an enveloped virus upon binding to the host cell.
  J Virol, 82, 10429-10435.  
18032483 E.Lazear, A.Carfi, J.C.Whitbeck, T.M.Cairns, C.Krummenacher, G.H.Cohen, and R.J.Eisenberg (2008).
Engineered disulfide bonds in herpes simplex virus type 1 gD separate receptor binding from fusion initiation and viral entry.
  J Virol, 82, 700-709.  
18568847 J.M.White, S.E.Delos, M.Brecher, and K.Schornberg (2008).
Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme.
  Crit Rev Biochem Mol Biol, 43, 189-219.  
18949019 J.R.Sedý, P.G.Spear, and C.F.Ware (2008).
Cross-regulation between herpesviruses and the TNF superfamily members.
  Nat Rev Immunol, 8, 861-873.  
18076965 K.M.Stiles, R.S.Milne, G.H.Cohen, R.J.Eisenberg, and C.Krummenacher (2008).
The herpes simplex virus receptor nectin-1 is down-regulated after trans-interaction with glycoprotein D.
  Virology, 373, 98.  
18474550 L.Gillet, S.Colaco, and P.G.Stevenson (2008).
Glycoprotein B switches conformation during murid herpesvirus 4 entry.
  J Gen Virol, 89, 1352-1363.  
18684832 L.Menotti, A.Cerretani, H.Hengel, and G.Campadelli-Fiume (2008).
Construction of a fully retargeted herpes simplex virus 1 recombinant capable of entering cells solely via human epidermal growth factor receptor 2.
  J Virol, 82, 10153-10161.  
18193057 M.O.Lasaro, N.Tatsis, S.E.Hensley, J.C.Whitbeck, S.W.Lin, J.J.Rux, E.J.Wherry, G.H.Cohen, R.J.Eisenberg, and H.C.Ertl (2008).
Targeting of antigen to the herpesvirus entry mediator augments primary adaptive immune responses.
  Nat Med, 14, 205-212.  
18671825 M.T.Sciortino, M.A.Medici, F.Marino-Merlo, D.Zaccaria, M.Giuffrè-Cuculletto, A.Venuti, S.Grelli, and A.Mastino (2008).
Involvement of HVEM receptor in activation of nuclear factor kappaB by herpes simplex virus 1 glycoprotein D.
  Cell Microbiol, 10, 2297-2311.  
18391029 R.Akkarawongsa, T.B.Potocky, E.P.English, S.H.Gellman, and C.R.Brandt (2008).
Inhibition of herpes simplex virus type 1 infection by cationic beta-peptides.
  Antimicrob Agents Chemother, 52, 2120-2129.  
18243431 S.Awasthi, J.M.Lubinski, R.J.Eisenberg, G.H.Cohen, and H.M.Friedman (2008).
An HSV-1 gD mutant virus as an entry-impaired live virus vaccine.
  Vaccine, 26, 1195-1203.  
18678872 S.Galdiero, A.Falanga, M.Vitiello, L.Raiola, R.Fattorusso, H.Browne, C.Pedone, C.Isernia, and M.Galdiero (2008).
Analysis of a membrane interacting region of herpes simplex virus type 1 glycoprotein H.
  J Biol Chem, 283, 29993-30009.  
18311743 S.Galdiero, M.Vitiello, M.D'Isanto, A.Falanga, M.Cantisani, H.Browne, C.Pedone, and M.Galdiero (2008).
The identification and characterization of fusogenic domains in herpes virus glycoprotein B molecules.
  Chembiochem, 9, 758-767.  
18800055 S.R.Wu, M.Sjöberg, M.Wallin, B.Lindqvist, M.Ekström, H.Hebert, P.J.Koeck, and H.Garoff (2008).
Turning of the receptor-binding domains opens up the murine leukaemia virus Env for membrane fusion.
  EMBO J, 27, 2799-2808.  
19122386 T.Satoh, and H.Arase (2008).
HSV-1 infection through inhibitory receptor, PILRalpha.
  Uirusu, 58, 27-36.  
18358807 T.Satoh, J.Arii, T.Suenaga, J.Wang, A.Kogure, J.Uehori, N.Arase, I.Shiratori, S.Tanaka, Y.Kawaguchi, P.G.Spear, L.L.Lanier, and H.Arase (2008).
PILRalpha is a herpes simplex virus-1 entry coreceptor that associates with glycoprotein B.
  Cell, 132, 935-944.  
17581996 A.N.Kirschner, A.S.Lowrey, R.Longnecker, and T.S.Jardetzky (2007).
Binding-site interactions between Epstein-Barr virus fusion proteins gp42 and gH/gL reveal a peptide that inhibits both epithelial and B-cell membrane fusion.
  J Virol, 81, 9216-9229.  
17295428 A.Reske, G.Pollara, C.Krummenacher, B.M.Chain, and D.R.Katz (2007).
Understanding HSV-1 entry glycoproteins.
  Rev Med Virol, 17, 205-215.  
17314168 B.P.Hannah, E.E.Heldwein, F.C.Bender, G.H.Cohen, and R.J.Eisenberg (2007).
Mutational evidence of internal fusion loops in herpes simplex virus glycoprotein B.
  J Virol, 81, 4858-4865.  
17670828 E.Avitabile, C.Forghieri, and G.Campadelli-Fiume (2007).
Complexes between herpes simplex virus glycoproteins gD, gB, and gH detected in cells by complementation of split enhanced green fluorescent protein.
  J Virol, 81, 11532-11537.  
17666526 E.Lin, and P.G.Spear (2007).
Random linker-insertion mutagenesis to identify functional domains of herpes simplex virus type 1 glycoprotein B.
  Proc Natl Acad Sci U S A, 104, 13140-13145.  
17267495 F.C.Bender, M.Samanta, E.E.Heldwein, Leon, E.Bilman, H.Lou, J.C.Whitbeck, R.J.Eisenberg, and G.H.Cohen (2007).
Antigenic and mutational analyses of herpes simplex virus glycoprotein B reveal four functional regions.
  J Virol, 81, 3827-3841.  
17573668 G.Campadelli-Fiume, M.Amasio, E.Avitabile, A.Cerretani, C.Forghieri, T.Gianni, and L.Menotti (2007).
The multipartite system that mediates entry of herpes simplex virus into the cell.
  Rev Med Virol, 17, 313-326.  
17360490 G.Zhou, and B.Roizman (2007).
Separation of receptor-binding and profusogenic domains of glycoprotein D of herpes simplex virus 1 into distinct interacting proteins.
  Proc Natl Acad Sci U S A, 104, 4142-4146.  
  18005714 J.M.Taylor, E.Lin, N.Susmarski, M.Yoon, A.Zago, C.F.Ware, K.Pfeffer, J.Miyoshi, Y.Takai, and P.G.Spear (2007).
Alternative entry receptors for herpes simplex virus and their roles in disease.
  Cell Host Microbe, 2, 19-28.  
17387010 J.T.Huiskonen, and S.J.Butcher (2007).
Membrane-containing viruses with icosahedrally symmetric capsids.
  Curr Opin Struct Biol, 17, 229-236.  
17406671 L.Gillet, H.Adler, and P.G.Stevenson (2007).
Glycosaminoglycan interactions in murine gammaherpesvirus-68 infection.
  PLoS ONE, 2, e347.  
17898071 L.Gillet, and P.G.Stevenson (2007).
Evidence for a multiprotein gamma-2 herpesvirus entry complex.
  J Virol, 81, 13082-13091.  
17157347 M.Tsvitov, A.R.Frampton, W.A.Shah, S.K.Wendell, A.Ozuer, Z.Kapacee, W.F.Goins, J.B.Cohen, and J.C.Glorioso (2007).
Characterization of soluble glycoprotein D-mediated herpes simplex virus type 1 infection.
  Virology, 360, 477-491.  
17496024 O.J.Brown, S.A.Lopez, A.O.Fuller, and T.Goodson (2007).
Formation and reversible dissociation of coiled coil of peptide to the C-terminus of the HSV B5 protein: a time-resolved spectroscopic analysis.
  Biophys J, 93, 1068-1078.  
17299053 R.P.Subramanian, and R.J.Geraghty (2007).
Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B.
  Proc Natl Acad Sci U S A, 104, 2903-2908.  
17458915 S.Galdiero, A.Falanga, M.Vitiello, M.D'Isanto, C.Collins, V.Orrei, H.Browne, C.Pedone, and M.Galdiero (2007).
Evidence for a role of the membrane-proximal region of herpes simplex virus Type 1 glycoprotein H in membrane fusion and virus inhibition.
  Chembiochem, 8, 885-895.  
17344290 T.M.Cairns, L.S.Friedman, H.Lou, J.C.Whitbeck, M.S.Shaner, G.H.Cohen, and R.J.Eisenberg (2007).
N-terminal mutants of herpes simplex virus type 2 gH are transported without gL but require gL for function.
  J Virol, 81, 5102-5111.  
16840698 E.E.Heldwein, H.Lou, F.C.Bender, G.H.Cohen, R.J.Eisenberg, and S.C.Harrison (2006).
Crystal structure of glycoprotein B from herpes simplex virus 1.
  Science, 313, 217-220.
PDB code: 2gum
17016458 F.A.Rey (2006).
Molecular gymnastics at the herpesvirus surface.
  EMBO Rep, 7, 1000-1005.  
16554374 G.Zhou, and B.Roizman (2006).
Construction and properties of a herpes simplex virus 1 designed to enter cells solely via the IL-13alpha2 receptor.
  Proc Natl Acad Sci U S A, 103, 5508-5513.  
16932752 K.M.Murphy, C.A.Nelson, and J.R.Sedý (2006).
Balancing co-stimulation and inhibition with BTLA and HVEM.
  Nat Rev Immunol, 6, 671-681.  
16699034 L.Menotti, A.Cerretani, and G.Campadelli-Fiume (2006).
A herpes simplex virus recombinant that exhibits a single-chain antibody to HER2/neu enters cells through the mammary tumor receptor, independently of the gD receptors.
  J Virol, 80, 5531-5539.  
  17192179 M.G.Delboy, J.L.Patterson, A.M.Hollander, and A.V.Nicola (2006).
Nectin-2-mediated entry of a syncytial strain of herpes simplex virus via pH-independent fusion with the plasma membrane of Chinese hamster ovary cells.
  Virol J, 3, 105.  
17125150 R.L.Rich, and D.G.Myszka (2006).
Survey of the year 2005 commercial optical biosensor literature.
  J Mol Recognit, 19, 478-534.  
16474129 T.Gianni, A.Piccoli, C.Bertucci, and G.Campadelli-Fiume (2006).
Heptad repeat 2 in herpes simplex virus 1 gH interacts with heptad repeat 1 and is critical for virus entry and fusion.
  J Virol, 80, 2216-2224.  
16973744 T.Gianni, C.Forghieri, and G.Campadelli-Fiume (2006).
The herpesvirus glycoproteins B and H.L are sequentially recruited to the receptor-bound gD to effect membrane fusion at virus entry.
  Proc Natl Acad Sci U S A, 103, 14572-14577.  
16873275 T.Gianni, R.Fato, C.Bergamini, G.Lenaz, and G.Campadelli-Fiume (2006).
Hydrophobic alpha-helices 1 and 2 of herpes simplex virus gH interact with lipids, and their mimetic peptides enhance virus infection and fusion.
  J Virol, 80, 8190-8198.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.