6CEX

Crystal structure of the A/Hong Kong/1/1968 (H3N2) influenza virus hemagglutinin in complex with small molecule N-Cyclohexyltaurine

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.57 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.172 

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Ligand Structure Quality Assessment 


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


Literature

A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin.

Kadam, R.U., Wilson, I.A.

(2018) Proc Natl Acad Sci U S A 115: 4240-4245

  • DOI: https://doi.org/10.1073/pnas.1801999115
  • Primary Citation of Related Structures:  
    6CEX, 6CF5

  • PubMed Abstract: 

    The influenza virus hemagglutinin (HA) glycoprotein mediates receptor binding and membrane fusion during viral entry in host cells. Blocking these key steps in viral infection has applications for development of novel antiinfluenza therapeutics as well as vaccines. However, the lack of structural information on how small molecules can gain a foothold in the small, shallow receptor-binding site (RBS) has hindered drug design against this important target on the viral pathogen. Here, we report on the serendipitous crystallization-based discovery of a small-molecule N -cyclohexyltaurine, commonly known as the buffering agent CHES, that is able to bind to both group-1 and group-2 HAs of influenza A viruses. X-ray structural characterization of group-1 H5N1 A/Vietnam/1203/2004 (H5/Viet) and group-2 H3N2 A/Hong Kong/1/1968 (H3/HK68) HAs at 2.0-Å and 2.57-Å resolution, respectively, revealed that N -cyclohexyltaurine binds to the heart of the conserved HA RBS. N -cyclohexyltaurine mimics the binding mode of the natural receptor sialic acid and RBS-targeting bnAbs through formation of similar hydrogen bonds and CH-π interactions with the HA. In H3/HK68, N -cyclohexyltaurine also binds to a conserved pocket in the stem region, thereby exhibiting a dual-binding mode in group-2 HAs. These long-awaited structural insights into RBS recognition by a noncarbohydrate-based small molecule enhance our knowledge of how to target this important functional site and can serve as a template to guide the development of novel broad-spectrum small-molecule therapeutics against influenza virus.

    • Organizational Affiliation: 

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hemagglutinin
A, C, E
323Influenza A virus (A/Hong Kong/1/1968(H3N2))Mutation(s): 0 
Gene Names: HA
UniProt
Find proteins for Q91MA7 (Influenza A virus (strain A/Hong Kong/1/1968 H3N2))
Explore Q91MA7 
Go to UniProtKB:  Q91MA7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ91MA7
Sequence Annotations
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  • Reference Sequence
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(by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Hemagglutinin
B, D, F
174Influenza A virus (A/nt/60/1968(H3N2))Mutation(s): 0 
Gene Names: HA
UniProt
Find proteins for P03436 (Influenza A virus (strain A/Northern Territory/60/1968 H3N2))
Explore P03436 
Go to UniProtKB:  P03436
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03436
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

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Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
G, K
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G15407YE
GlyCosmos:  G15407YE
GlyGen:  G15407YE
Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
H, I, J, L, M
H, I, J, L, M, O
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Entity ID: 5
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
N
5N-Glycosylation
Glycosylation Resources
GlyTouCan:  G22768VO
GlyCosmos:  G22768VO
GlyGen:  G22768VO
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG
Download Ideal Coordinates CCD File 
EA [auth E]
FA [auth E]
GA [auth E]
IA [auth F]
Q [auth A]
EA [auth E],
FA [auth E],
GA [auth E],
IA [auth F],
Q [auth A],
R [auth A],
S [auth A],
W [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
NHE
Query on NHE
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DA [auth E]
HA [auth F]
P [auth A]
V [auth B]
Y [auth C]
DA [auth E],
HA [auth F],
P [auth A],
V [auth B],
Y [auth C],
Z [auth C]
2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID
C8 H17 N O3 S
MKWKNSIESPFAQN-UHFFFAOYSA-N
SO4
Query on SO4
Download Ideal Coordinates CCD File 
BA [auth D]
CA [auth D]
JA [auth F]
T [auth A]
U [auth A]
BA [auth D],
CA [auth D],
JA [auth F],
T [auth A],
U [auth A],
X [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL
Download Ideal Coordinates CCD File 
AA [auth C]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.57 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.172 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 104.846α = 90
b = 151.672β = 90
c = 346.81γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesR56 AI117675

Revision History  (Full details and data files)

  • Version 1.0: 2018-04-04
    Type: Initial release
  • Version 1.1: 2018-04-18
    Changes: Data collection, Database references
  • Version 1.2: 2018-05-02
    Changes: Data collection, Database references
  • Version 1.3: 2019-02-20
    Changes: Author supporting evidence, Data collection
  • Version 1.4: 2019-12-18
    Changes: Author supporting evidence
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary