6DC3

RSV prefusion F bound to RSD5 Fab

PDB DOI: https://doi.org/10.2210/pdb6DC3/pdb

Classification: IMMUNE SYSTEM
Organism(s): Homo sapiens, Human respiratory syncytial virus A2, Human immunodeficiency virus 1, unidentified
Expression System: Homo sapiens
Mutation(s): Yes

Deposited: 2018-05-04 Released: 2019-07-10
Deposition Author(s): Battles, M.B., McLellan, J.S., Jones, H.J.
Funding Organization(s): National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 3.50 Å
R-Value Free: 0.205
R-Value Work: 0.183
R-Value Observed: 0.184

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Alternative conformations of a major antigenic site on RSV F.

Jones, H.G., Battles, M.B., Lin, C.C., Bianchi, S., Corti, D., McLellan, J.S.

(2019) PLoS Pathog 15: e1007944-e1007944

PubMed: 31306469 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1371/journal.ppat.1007944
Primary Citation of Related Structures:
6DC3, 6DC4, 6DC5

PubMed Abstract:
The respiratory syncytial virus (RSV) fusion (F) glycoprotein is a major target of neutralizing antibodies arising from natural infection, and antibodies that specifically bind to the prefusion conformation of RSV F generally demonstrate the greatest neutralization potency. Prefusion-stabilized RSV F variants have been engineered as vaccine antigens, but crystal structures of these variants have revealed conformational differences in a key antigenic site located at the apex of the trimer, referred to as antigenic site Ø. Currently, it is unclear if flexibility in this region is an inherent property of prefusion RSV F or if it is related to inadequate stabilization of site Ø in the engineered variants. Therefore, we set out to investigate the conformational flexibility of antigenic site Ø, as well as the ability of the human immune system to recognize alternative conformations of this site, by determining crystal structures of prefusion RSV F bound to neutralizing human-derived antibodies AM22 and RSD5. Both antibodies bound with high affinity and were specific for the prefusion conformation of RSV F. Crystal structures of the complexes revealed that the antibodies recognized distinct conformations of antigenic site Ø, each diverging at a conserved proline residue located in the middle of an α-helix. These data suggest that antigenic site Ø exists as an ensemble of conformations, with individual antibodies recognizing discrete states. Collectively, these results have implications for the refolding of pneumovirus and paramyxovirus fusion proteins and should inform development of prefusion-stabilized RSV F vaccine candidates.

Organizational Affiliation

Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

Macromolecule Content

Total Structure Weight: 112.18 kDa
Atom Count: 6,890
Modelled Residue Count: 894
Deposited Residue Count: 1,014
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 RSD5-Germline Heavy Chain	A [auth H]	230	Homo sapiens	Mutation(s): 0
UniProt
Find proteins for Q6N089 (Homo sapiens) Explore Q6N089 Go to UniProtKB: Q6N089
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q6N089
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Fab RSD5-Germline Light Chain	B [auth L]	216	Homo sapiens	Mutation(s): 0
UniProt
Find proteins for Q8N355 (Homo sapiens) Explore Q8N355 Go to UniProtKB: Q8N355
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q8N355
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
RSV fusion glycoprotein	C [auth F]	568	Human respiratory syncytial virus A2, Human immunodeficiency virus 1, unidentified This entity is chimeric	Mutation(s): 7
UniProt
Find proteins for M1E1E4 (Human immunodeficiency virus 1) Explore M1E1E4 Go to UniProtKB: M1E1E4
Find proteins for P03420 (Human respiratory syncytial virus A (strain A2)) Explore P03420 Go to UniProtKB: P03420
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Groups	M1E1E4P03420
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain L [auth F] SDF format, chain M [auth F] MOL2 format, chain L [auth F] MOL2 format, chain M [auth F]	L [auth F], M [auth F]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain L [auth F] Focus chain M [auth F] Interactions & Density Focus chain L [auth F] Focus chain M [auth F]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain D [auth H] SDF format, chain E [auth L] SDF format, chain F [auth L] SDF format, chain G [auth L] SDF format, chain H [auth L] SDF format, chain I [auth L] SDF format, chain J [auth L] SDF format, chain K [auth L] SDF format, chain N [auth F] SDF format, chain O [auth F] SDF format, chain P [auth F] SDF format, chain Q [auth F] SDF format, chain R [auth F] MOL2 format, chain D [auth H] MOL2 format, chain E [auth L] MOL2 format, chain F [auth L] MOL2 format, chain G [auth L] MOL2 format, chain H [auth L] MOL2 format, chain I [auth L] MOL2 format, chain J [auth L] MOL2 format, chain K [auth L] MOL2 format, chain N [auth F] MOL2 format, chain O [auth F] MOL2 format, chain P [auth F] MOL2 format, chain Q [auth F] MOL2 format, chain R [auth F]	D [auth H] E [auth L] F [auth L] G [auth L] H [auth L] D [auth H], E [auth L], F [auth L], G [auth L], H [auth L], I [auth L], J [auth L], K [auth L], N [auth F], O [auth F], P [auth F], Q [auth F], R [auth F]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain D [auth H] Focus chain E [auth L] Focus chain F [auth L] Focus chain G [auth L] Focus chain H [auth L] Focus chain I [auth L] Focus chain J [auth L] Focus chain K [auth L] Focus chain N [auth F] Focus chain O [auth F] Focus chain P [auth F] Focus chain Q [auth F] Focus chain R [auth F] Interactions & Density Focus chain D [auth H] Focus chain E [auth L] Focus chain F [auth L] Focus chain G [auth L] Focus chain H [auth L] Focus chain I [auth L] Focus chain J [auth L] Focus chain K [auth L] Focus chain N [auth F] Focus chain O [auth F] Focus chain P [auth F] Focus chain Q [auth F] Focus chain R [auth F]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 3.50 Å
R-Value Free: 0.205
R-Value Work: 0.183
R-Value Observed: 0.184
Space Group: I 2 3

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 270.32	α = 90
b = 270.32	β = 90
c = 270.32	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
MOSFLM	data reduction
Aimless	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2019-07-10

Deposition Author(s):

Battles, M.B.

McLellan, J.S.

Jones, H.J.

Funding Organization	Location	Grant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	United States	P20GM113132

Revision History (Full details and data files)

Version 1.0: 2019-07-10
Type: Initial release
Version 1.1: 2020-01-01
Changes: Author supporting evidence
Version 1.2: 2020-01-22
Changes: Database references
Version 1.3: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Data collection, Derived calculations, Structure summary
Version 1.4: 2023-10-04
Changes: Data collection, Database references, Refinement description, Structure summary