4EWS

Crystal structure of cholesteryl ester transfer protein in complex with inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.59 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.215 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Crystal structures of cholesteryl ester transfer protein in complex with inhibitors.

Liu, S.Mistry, A.Reynolds, J.M.Lloyd, D.B.Griffor, M.C.Perry, D.A.Ruggeri, R.B.Clark, R.W.Qiu, X.

(2012) J Biol Chem 287: 37321-37329

  • DOI: https://doi.org/10.1074/jbc.M112.380063
  • Primary Citation of Related Structures:  
    4EWS, 4F2A

  • PubMed Abstract: 

    Human plasma cholesteryl ester transfer protein (CETP) transports cholesteryl ester from the antiatherogenic high-density lipoproteins (HDL) to the proatherogenic low-density and very low-density lipoproteins (LDL and VLDL). Inhibition of CETP has been shown to raise human plasma HDL cholesterol (HDL-C) levels and is potentially a novel approach for the prevention of cardiovascular diseases. Here, we report the crystal structures of CETP in complex with torcetrapib, a CETP inhibitor that has been tested in phase 3 clinical trials, and compound 2, an analog from a structurally distinct inhibitor series. In both crystal structures, the inhibitors are buried deeply within the protein, shifting the bound cholesteryl ester in the N-terminal pocket of the long hydrophobic tunnel and displacing the phospholipid from that pocket. The lipids in the C-terminal pocket of the hydrophobic tunnel remain unchanged. The inhibitors are positioned near the narrowing neck of the hydrophobic tunnel of CETP and thus block the connection between the N- and C-terminal pockets. These structures illuminate the unusual inhibition mechanism of these compounds and support the tunnel mechanism for neutral lipid transfer by CETP. These highly lipophilic inhibitors bind mainly through extensive hydrophobic interactions with the protein and the shifted cholesteryl ester molecule. However, polar residues, such as Ser-230 and His-232, are also found in the inhibitor binding site. An enhanced understanding of the inhibitor binding site may provide opportunities to design novel CETP inhibitors possessing more drug-like physical properties, distinct modes of action, or alternative pharmacological profiles.


  • Organizational Affiliation

    Department of Structural Biology & Biophysics, Pfizer Groton Laboratories, Groton, Connecticut 06340, USA. shenping.liu@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CETP476Homo sapiensMutation(s): 6 
UniProt & NIH Common Fund Data Resources
Find proteins for P11597 (Homo sapiens)
Explore P11597 
Go to UniProtKB:  P11597
PHAROS:  P11597
GTEx:  ENSG00000087237 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11597
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose
B
4N-Glycosylation
Glycosylation Resources
GlyTouCan:  G47477HI
GlyCosmos:  G47477HI
GlyGen:  G47477HI
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
DLP
Query on DLP

Download Ideal Coordinates CCD File 
E [auth A]1,2-DILINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
C44 H80 N O8 P
FVXDQWZBHIXIEJ-LNDKUQBDSA-N
2OB
Query on 2OB

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
CHOLESTERYL OLEATE
C45 H78 O2
RJECHNNFRHZQKU-RMUVNZEASA-N
0RP
Query on 0RP

Download Ideal Coordinates CCD File 
I [auth A]ethyl (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl](methoxycarbonyl)amino}-2-ethyl-6-(trifluoromethyl)-3,4-dihydroquinoline-1(2H )-carboxylate
C26 H25 F9 N2 O4
CMSGWTNRGKRWGS-NQIIRXRSSA-N
PGE
Query on PGE

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A]
TRIETHYLENE GLYCOL
C6 H14 O4
ZIBGPFATKBEMQZ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
H [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
0RP BindingDB:  4EWS IC50: min: 3, max: 110 (nM) from 8 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.59 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.215 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.6α = 90
b = 69.323β = 90
c = 188.233γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
BUSTERrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-09-05
    Type: Initial release
  • Version 1.1: 2012-09-26
    Changes: Database references
  • Version 1.2: 2012-11-14
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Structure summary
  • Version 2.1: 2023-09-13
    Changes: Data collection, Database references, Refinement description, Structure summary