6E4Y

Anti-PCSK9 fab 6E2 bound to the N-terminal peptide from PCSK9, unmodified


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Identification of a Helical Segment within the Intrinsically Disordered Region of the PCSK9 Prodomain.

Ultsch, M.Li, W.Eigenbrot, C.Di Lello, P.Lipari, M.T.Gerhardy, S.AhYoung, A.P.Quinn, J.Franke, Y.Chen, Y.Kong Beltran, M.Peterson, A.Kirchhofer, D.

(2019) J Mol Biol 431: 885-903

  • DOI: https://doi.org/10.1016/j.jmb.2018.11.025
  • Primary Citation of Related Structures:  
    6E4Y, 6E4Z, 6MV5

  • PubMed Abstract: 

    Proprotein convertase subtilisin/kexin 9 (PCSK9) is a key regulator of lipid metabolism by degrading liver LDL receptors. Structural studies have provided molecular details of PCSK9 function. However, the N-terminal acidic stretch of the PCSK9 prodomain (Q31-T60) has eluded structural investigation, since it is in a disordered state. The interest in this region is intensified by the presence of human missense mutations associated with low and high LDL-c levels (E32K, D35Y, and R46L, respectively), as well as two posttranslationally modified sites, sulfated Y38 and phosphorylated S47. Herein we show that a segment within this region undergoes disorder-to-order transition. Experiments with acidic stretch-derived peptides demonstrated that the folding is centered at the segment Y38-L45, which adopts an α-helix as determined by NMR analysis of free peptides and by X-ray crystallography of peptides in complex with antibody 6E2 (Ab6E2). In the Fab6E2-peptide complexes, the structured region features a central 2 1/4-turn α-helix and encompasses up to 2/3 of the length of the acidic stretch, including the missense mutations and posttranslationally modified sites. Experiments with helix-breaking proline substitutions in peptides and in PCSK9 protein indicated that Ab6E2 specifically recognizes the helical conformation of the acidic stretch. Therefore, the observed quantitative binding of Ab6E2 to native PCSK9 from various cell lines suggests that the disorder-to-order transition is a true feature of PCSK9 and not limited to peptides. Because the helix provides a constrained spatial orientation of the missense mutations and the posttranslationally modified residues, it is probable that their biological functions take place in the context of an ordered conformational state.


  • Organizational Affiliation

    Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
6E2 heavy chainA [auth H]224Mus musculusMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
6E2 light chainB [auth L]219Mus musculusMutation(s): 0 
UniProt
Find proteins for A0A097PUG4 (Mus musculus)
Explore A0A097PUG4 
Go to UniProtKB:  A0A097PUG4
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UniProt GroupA0A097PUG4
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Proprotein convertase subtilisin/kexin type 9C [auth P]22Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q8NBP7 (Homo sapiens)
Explore Q8NBP7 
Go to UniProtKB:  Q8NBP7
PHAROS:  Q8NBP7
GTEx:  ENSG00000169174 
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UniProt GroupQ8NBP7
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.378α = 90
b = 100.527β = 90
c = 86.715γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-04-10
    Type: Initial release
  • Version 1.1: 2023-10-11
    Changes: Data collection, Database references, Derived calculations, Refinement description