PDBsum entry 3ixt

Immune system

PDB id: 3ixt

Contents

Protein chains

211 a.a. *

213 a.a. *

26 a.a. *

Ligands

EDO ×3

Waters ×150

* Residue conservation analysis

PDB id:

3ixt

Name:

Immune system

Title:

Crystal structure of motavizumab fab bound to peptide epitope

Structure:

Motavizumab fab light chain. Chain: l, b. Engineered: yes. Motavizumab fab heavy chain. Chain: h, a. Engineered: yes. Fusion glycoprotein f1. Chain: p, c. Fragment: sequence database residues 254-277.

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: 293f cells. Other_details: humanized-mouse antibody. Human respiratory syncytial virus. Organism_taxid: 11259.

Resolution:

2.75Å R-factor: 0.216 R-free: 0.274

Authors:

J.S.Mclellan,M.Chen,A.Kim,Y.Yang,B.S.Graham,P.D.Kwong

Key ref:

J.S.McLellan et al. (2010). Structural basis of respiratory syncytial virus neutralization by motavizumab. Nat Struct Biol, 17, 248-250. PubMed id: 20098425 DOI: 10.1038/nsmb.1723

Date:

04-Sep-09 Release date: 19-Jan-10

Protein chains

No UniProt id for this chain

Struc: 211 a.a.

Protein chains

No UniProt id for this chain

Struc: 213 a.a.

Protein chains

P03420  (FUS_HRSVA) -  Fusion glycoprotein F0 from Human respiratory syncytial virus A (strain A2)

Seq: 574 a.a.

Struc: 25 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1038/nsmb.1723

Nat Struct Biol 17:248-250 (2010)

PubMed id: 20098425

Structural basis of respiratory syncytial virus neutralization by motavizumab.

J.S.McLellan, M.Chen, A.Kim, Y.Yang, B.S.Graham, P.D.Kwong.

ABSTRACT

Motavizumab is approximately tenfold more potent than its predecessor, palivizumab (Synagis), the FDA-approved monoclonal antibody used to prevent respiratory syncytial virus (RSV) infection. The structure of motavizumab in complex with a 24-residue peptide corresponding to its epitope on the RSV fusion (F) glycoprotein reveals the structural basis for this greater potency. Modeling suggests that motavizumab recognizes a different quaternary configuration of the F glycoprotein than that observed in a homologous structure.

Selected figure(s)

Figure 1.
(a) RSV neutralization curves for palivizumab and motavizumab IgG as determined by a flow cytometric assay. (b) Surface representation of the Fab and ribbon representation of the peptide, viewed looking down at the CDRs and a 90° rotation about the horizontal axis from c and d. (c) Interactions between the peptide and six Fab CDRs. Side chains are shown for those residues making intermolecular interactions. Dashed lines represent hydrogen bonds. Residues in the hydrophobic patch on the heavy chain are shown with transparent surfaces. These include Trp52 and Trp53 on the right and Ile97, Phe98 and Phe100 on the left. (d) Motavizumab mutations that alter affinity to the F glycoprotein. Side chains are shown for those Fab residues that increase affinity by directly contacting the peptide (red), by altering the position of residues that directly contact the peptide (cyan) or by binding to the F glycoprotein outside the primary epitope or enhancing long-range electrostatic interactions (magenta). Fab residues in yellow decrease the affinity for the F glycoprotein but increase in vivo potency compared to an earlier version of motavizumab.

Figure 2.
(a) Superposition of the motavizumab-bound peptide (gray) and residues 229–252 of the PIV5 F glycoprotein structure (red). (b) Ribbon representation of the model of motavizumab Fab (green and blue) bound to the PIV5 F glycoprotein monomer (tan) via the superposition shown in a. (c) Same as b, except the entire PIV5 F glycoprotein trimer is shown (tan, green, pink). (d) Magnification of the boxed area shown in c. (e) Gel filtration elution profile and corresponding Coomassie blue–stained SDS-PAGE gel of the RSV F[0] Fd glycoprotein. (f) Gel filtration elution profile and corresponding Coomassie blue–stained SDS-PAGE gel of a mixture of RSV F[0] Fd glycoprotein and excess palivizumab Fab. Densitometric analysis of the gel yields a ratio of 2.97 Fabs per trimer.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2010, 17, 248-250) copyright 2010.