3MME

Structure and functional dissection of PG16, an antibody with broad and potent neutralization of HIV-1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.97 Å
  • R-Value Free: 0.317 
  • R-Value Work: 0.256 
  • R-Value Observed: 0.259 

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This is version 2.1 of the entry. See complete history


Literature

Crystal structure of PG16 and chimeric dissection with somatically related PG9: structure-function analysis of two quaternary-specific antibodies that effectively neutralize HIV-1.

Pancera, M.McLellan, J.S.Wu, X.Zhu, J.Changela, A.Schmidt, S.D.Yang, Y.Zhou, T.Phogat, S.Mascola, J.R.Kwong, P.D.

(2010) J Virol 84: 8098-8110

  • DOI: https://doi.org/10.1128/JVI.00966-10
  • Primary Citation of Related Structures:  
    3LRS, 3MME

  • PubMed Abstract: 

    HIV-1 resists neutralization by most antibodies. Two somatically related human antibodies, PG9 and PG16, however, each neutralize 70 to 80% of circulating HIV-1 isolates. Here we present the structure of the antigen-binding fragment of PG16 in monoclinic and orthorhombic lattices at 2.4 and 4.0 A, respectively, and use a combination of structural analysis, paratope dissection, and neutralization assessment to determine the functional relevance of three unusual PG9/PG16 features: N-linked glycosylation, extensive affinity maturation, and a heavy chain-third complementarity-determining region (CDR H3) that is one of the longest observed in human antibodies. Glycosylation extended off the side of the light chain variable domain and was not required for neutralization. The CDR H3 formed an axe-shaped subdomain, which comprised 42% of the CDR surface, with the axe head looming approximately 20 A above the other combining loops. Comprehensive sets of chimeric swaps between PG9 and PG16 of light chain, heavy chain, and CDR H3 were employed to decipher structure-function relationships. Chimeric swaps generally complemented functionally, with differences in PG9/PG16 neutralization related primarily to residue differences in CDR H3. Meanwhile, chimeric reversions to genomic V genes showed isolate-dependent effects, with affinity maturation playing a significant role in augmenting neutralization breadth (P = 0.036) and potency (P < 0.0001). The structural and functional details of extraordinary CDR H3 and extensive affinity maturation provide insights into the neutralization mechanism of and the elicitation pathway for broadly neutralizing antibodies like PG9 and PG16.


  • Organizational Affiliation

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-3027, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PG16 HEAVY CHAIN FABA [auth H],
C [auth A],
E [auth C]
238Homo sapiensMutation(s): 0 
Entity Groups  
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
PG16 LIGHT CHAIN FABB [auth L],
D [auth B],
F [auth D]
216Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
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-glucopyranoseG [auth E]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-glucopyranoseH [auth F]2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
I [auth B]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.97 Å
  • R-Value Free: 0.317 
  • R-Value Work: 0.256 
  • R-Value Observed: 0.259 
  • Space Group: C 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 191.961α = 90
b = 230.804β = 90
c = 82.096γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-06-09
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-09-06
    Changes: Data collection, Database references, Refinement description, Structure summary