Structural highlights
Function
[GB_HCMVT] Envelope glycoprotein that plays a role in host cell entry, cell to-cell virus transmission, and fusion of infected cells. May be involved in the initial attachment via binding to heparan sulfate together with the gM/gN complex that binds heparin with higher affinity. Interacts with host integrin ITGB1, PDGFRA and EGFR that likely serve as postattachment entry receptors. Participates also in the fusion of viral and cellular membranes leading to virus entry into the host cell. Membrane fusion is mediated by the fusion machinery composed at least of gB and the heterodimer gH/gL (By similarity). Viral ligand for CD209/DC-SIGN. This interaction allows capture of viral particles by dendritic (DCs) cells and subsequent virus transmission to permissive cells. DCs are professional antigen presenting cells, critical for host immunity by inducing specific immune responses against a broad variety of pathogens. They act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. CMV subverts the migration properties of dendritic cells to gain access to target organs or susceptible cells.
Publication Abstract from PubMed
Human cytomegalovirus (HCMV) infections are life-threating to people with a compromised or immature immune system. Upon adhesion, fusion of the virus envelope with the host cell is initiated. In this step, the viral glycoprotein gB is considered to represent the major fusogen. Here, we present for the first time structural data on the binding of an anti-herpes virus antibody and describe the atomic interactions between the antigenic domain Dom-II of HCMV gB and the Fab fragment of the human antibody SM5-1. The crystal structure shows that SM5-1 binds Dom-II almost exclusively via only two CDRs, namely light chain CDR L1 and a 22-residue-long heavy chain CDR H3. Two contiguous segments of Dom-II are targeted by SM5-1, and the combining site includes a hydrophobic pocket on the Dom-II surface that is only partially filled by CDR H3 residues. SM5-1 belongs to a series of sequence-homologous anti-HCMV gB monoclonal antibodies that were isolated from the same donor at a single time point and that represent different maturation states. Analysis of amino acid substitutions in these antibodies in combination with molecular dynamics simulations show that key contributors to the picomolar affinity of SM5-1 do not directly interact with the antigen but significantly reduce the flexibility of CDR H3 in the bound and unbound state of SM5-1 through intramolecular side chain interactions. Thus, these residues most likely alleviate unfavorable binding entropies associated with extra-long CDR H3s, and this might represent a common strategy during antibody maturation. Models of entire HCMV gB in different conformational states hint that SM5-1 neutralizes HCMV either by blocking the pre- to postfusion transition of gB or by precluding the interaction with additional effectors such as the gH/gL complex.
Structural basis for the recognition of human cytomegalovirus glycoprotein B by a neutralizing human antibody.,Spindler N, Diestel U, Stump JD, Wiegers AK, Winkler TH, Sticht H, Mach M, Muller YA PLoS Pathog. 2014 Oct 9;10(10):e1004377. doi: 10.1371/journal.ppat.1004377., eCollection 2014 Oct. PMID:25299639[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Spindler N, Diestel U, Stump JD, Wiegers AK, Winkler TH, Sticht H, Mach M, Muller YA. Structural basis for the recognition of human cytomegalovirus glycoprotein B by a neutralizing human antibody. PLoS Pathog. 2014 Oct 9;10(10):e1004377. doi: 10.1371/journal.ppat.1004377., eCollection 2014 Oct. PMID:25299639 doi:https://dx.doi.org/10.1371/journal.ppat.1004377
