4U6V

Mechanisms of Neutralization of a Human Anti-Alpha Toxin Antibody

PDB DOI: https://doi.org/10.2210/pdb4U6V/pdb

Classification: IMMUNE SYSTEM
Organism(s): Homo sapiens, Staphylococcus aureus subsp. aureus TCH60
Expression System: Mammalian expression vector pBGSA, Staphylococcus aureus
Mutation(s): No

Deposited: 2014-07-29 Released: 2014-09-17
Deposition Author(s): Oganesyan, V.Y., Peng, L., Damschroder, M.M., Cheng, L., Sadowska, A., Tkaczyk, C., Sellman, B., Wu, H., Dall'Acqua, W.F.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.56 Å
R-Value Free: 0.235
R-Value Work: 0.198
R-Value Observed: 0.200

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

This is version 2.1 of the entry. See complete history.

Literature

Mechanisms of Neutralization of a Human Anti-alpha-toxin Antibody.

Oganesyan, V., Peng, L., Damschroder, M.M., Cheng, L., Sadowska, A., Tkaczyk, C., Sellman, B.R., Wu, H., Dall'Acqua, W.F.

(2014) J Biol Chem 289: 29874-29880

PubMed: 25210036 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1074/jbc.M114.601328
Primary Citation of Related Structures:
4U6V

PubMed Abstract:
MEDI4893 is a neutralizing human monoclonal antibody that targets α-toxin (AT) and is currently undergoing evaluation in the field of Staphylococcus aureus-mediated diseases. We have solved the crystal structure of MEDI4893 Fab bound to monomeric AT at a resolution of 2.56 Å and further characterized its epitope using various engineered AT variants. We have found that MEDI4893 recognizes a novel epitope in the so-called "rim" domain of AT and exerts its neutralizing effect through a dual mechanism. In particular, MEDI4893 not only sterically blocks binding of AT to its cell receptor but also prevents it from adopting a lytic heptameric trans-membrane conformation.

Organizational Affiliation

From the Departments of Antibody Discovery and Protein Engineering and [email protected].

Macromolecule Content

Total Structure Weight: 161.58 kDa
Atom Count: 11,052
Modelled Residue Count: 1,406
Deposited Residue Count: 1,462
Unique protein chains: 3

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Fab, antigen binding fragment, heavy chain	A [auth H], D [auth K]	225	Homo sapiens	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence

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Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Fab, antigen binding fragment, light chain	B [auth L], E [auth M]	213	Homo sapiens	Mutation(s): 0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
Alpha-hemolysin	C [auth A], F [auth B]	293	Staphylococcus aureus subsp. aureus TCH60	Mutation(s): 0
UniProt
Find proteins for Q2G1X0 (Staphylococcus aureus (strain NCTC 8325 / PS 47)) Explore Q2G1X0 Go to UniProtKB: Q2G1X0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q2G1X0
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain G [auth H] SDF format, chain H SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain L [auth K] MOL2 format, chain G [auth H] MOL2 format, chain H MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain L [auth K] mmCIF format, chain G [auth H] mmCIF format, chain H mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain L [auth K]	G [auth H] H I [auth A] J [auth A] K [auth A] G [auth H], H, I [auth A], J [auth A], K [auth A], L [auth K]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain G [auth H] Focus chain H Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth K] Interactions & Density Focus chain G [auth H] Focus chain H Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth K]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.56 Å
R-Value Free: 0.235
R-Value Work: 0.198
R-Value Observed: 0.200
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 85.524	α = 90
b = 148.505	β = 99.82
c = 93.824	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement

Structure Validation

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Entry History

Deposition Data

Released Date: 2014-09-17

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2014-09-17
Type: Initial release
Version 1.1: 2014-09-24
Changes: Database references
Version 1.2: 2014-11-05
Changes: Database references
Version 2.0: 2023-09-27
Changes: Atomic model, Data collection, Database references, Derived calculations, Other, Refinement description, Source and taxonomy
Version 2.1: 2024-11-20
Changes: Structure summary