4OT1

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

Summary for 4OT1

• Entry DOI: 10.2210/pdb4ot1/pdb
• Related: 4OSN 4OSU
• Descriptor: Envelope glycoprotein B, SM5-1 Fab Heavy Chain, SM5-1 Fab Light Chain, ... (6 entities in total)
• Functional Keywords: immunoglobulin, ph domain, antibody-antigen recognition, viral protein-immune system complex, viral protein/immune system
• Biological source: Human Cytomegalovirus (HHV-5); More
• Cellular location: Virion membrane ; Single-pass type I membrane protein : P13201
• Total number of polymer chains: 3
• Total formula weight: 62298.68

Authors

Diestel, U.,Muller, Y.A. (deposition date: 2014-02-13, release date: 2014-08-13, Last modification date: 2024-10-16)

Primary citation

Spindler, N.,Diestel, U.,Stump, J.D.,Wiegers, A.K.,Winkler, T.H.,Sticht, H.,Mach, M.,Muller, Y.A.
Structural basis for the recognition of human cytomegalovirus glycoprotein B by a neutralizing human antibody.
Plos Pathog., 10:e1004377-e1004377, 2014

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.

PubMed: 25299639
DOI: 10.1371/journal.ppat.1004377

Experimental method

X-RAY DIFFRACTION (2.11 Å)