4OT1

Structural Basis for the Recognition of Human Cytomegalovirus Glycoprotein B by the Neutralizing Human Antibody SM5-1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.174 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Structural basis for the recognition of human cytomegalovirus glycoprotein B by a neutralizing human antibody.

Spindler, N.Diestel, U.Stump, J.D.Wiegers, A.K.Winkler, T.H.Sticht, H.Mach, M.Muller, Y.A.

(2014) PLoS Pathog 10: e1004377-e1004377

  • DOI: https://doi.org/10.1371/journal.ppat.1004377
  • Primary Citation of Related Structures:  
    4OSU, 4OT1

  • PubMed Abstract: 

    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.


  • Organizational Affiliation

    Institut für Klinische und Molekulare Virologie, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Envelope glycoprotein B129Human herpesvirus 5 strain TowneMutation(s): 2 
Gene Names: gBUL55
UniProt
Find proteins for P13201 (Human cytomegalovirus (strain Towne))
Explore P13201 
Go to UniProtKB:  P13201
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP13201
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
SM5-1 Fab Heavy ChainB [auth H]234Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
SM5-1 Fab Light ChainC [auth L]215Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.174 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.071α = 90
b = 69.411β = 99.68
c = 100.991γ = 90
Software Package:
Software NamePurpose
mxdata collection
PHASERphasing
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-08-13
    Type: Initial release
  • Version 1.1: 2014-10-22
    Changes: Database references
  • Version 1.2: 2017-08-23
    Changes: Refinement description, Source and taxonomy