3TVU

Crystal Structure of the humanized carboxyltransferase domain of yeast Acetyl-coA caroxylase in complex with compound 3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-guided Inhibitor Design for Human Acetyl-coenzyme A Carboxylase by Interspecies Active Site Conversion.

Rajamohan, F.Marr, E.Reyes, A.R.Landro, J.A.Anderson, M.D.Corbett, J.W.Dirico, K.J.Harwood, J.H.Tu, M.Vajdos, F.F.

(2011) J Biol Chem 286: 41510-41519

  • DOI: https://doi.org/10.1074/jbc.M111.275396
  • Primary Citation of Related Structures:  
    3TV5, 3TVU, 3TVW, 3TZ3

  • PubMed Abstract: 

    Inhibition of acetyl-CoA carboxylases (ACCs), a crucial enzyme for fatty acid metabolism, has been shown to promote fatty acid oxidation and reduce body fat in animal models. Therefore, ACCs are attractive targets for structure-based inhibitor design, particularly the carboxyltransferase (CT) domain, which is the primary site for inhibitor interaction. We have cloned, expressed, and purified the CT domain of human ACC2 using baculovirus-mediated insect cell expression system. However, attempts to crystallize the human ACC2 CT domain have not been successful in our hands. Hence, we have been using the available crystal structure of yeast CT domain to design human ACC inhibitors. Unfortunately, as the selectivity of the lead series has increased against the full-length human enzyme, the potency against the yeast enzyme has decreased significantly. This loss of potency against the yeast enzyme correlated with a complete lack of binding of the human-specific compounds to crystals of the yeast CT domain. Here, we address this problem by converting nine key active site residues of the yeast CT domain to the corresponding human residues. The resulting humanized yeast ACC-CT (yCT-H9) protein exhibits biochemical and biophysical properties closer to the human CT domain and binding to human specific compounds. We report high resolution crystal structures of yCT-H9 complexed with inhibitors that show a preference for the human CT domain. These structures offer insights that explain the species selectivity of ACC inhibitors and may guide future drug design programs.


  • Organizational Affiliation

    Pfizer Global Research and Development, Groton, Connecticut 06340. Electronic address: francis.rajamohan@pfizer.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Acetyl-CoA carboxylase
A, B, C
769Saccharomyces cerevisiae S288CMutation(s): 9 
Gene Names: ACC1ABP2FAS3MTR7YNR016CN3175
EC: 6.4.1.2 (PDB Primary Data), 6.3.4.14 (PDB Primary Data)
UniProt
Find proteins for Q00955 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore Q00955 
Go to UniProtKB:  Q00955
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ00955
Sequence Annotations
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 246.985α = 90
b = 123.176β = 94.2
c = 146.157γ = 90
Software Package:
Software NamePurpose
d*TREKdata scaling
d*TREKdata reduction
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
BUSTERrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-10-19
    Type: Initial release
  • Version 1.1: 2011-12-14
    Changes: Database references
  • Version 1.2: 2018-01-24
    Changes: Structure summary
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description