5KKN

Crystal structure of human ACC2 BC domain in complex with ND-646, the primary amide of ND-630


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats.

Harriman, G.Greenwood, J.Bhat, S.Huang, X.Wang, R.Paul, D.Tong, L.Saha, A.K.Westlin, W.F.Kapeller, R.Harwood, H.J.

(2016) Proc Natl Acad Sci U S A 113: E1796-E1805

  • DOI: https://doi.org/10.1073/pnas.1520686113
  • Primary Citation of Related Structures:  
    5KKN

  • PubMed Abstract: 

    Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.


  • Organizational Affiliation

    Nimbus Therapeutics, Cambridge, MA 02141;


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Acetyl-CoA carboxylase 2A [auth B],
B [auth C]
540Homo sapiensMutation(s): 0 
Gene Names: ACACBACC2ACCB
EC: 6.4.1.2 (PDB Primary Data), 6.3.4.14 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for O00763 (Homo sapiens)
Explore O00763 
Go to UniProtKB:  O00763
PHAROS:  O00763
GTEx:  ENSG00000076555 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO00763
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6U3
Query on 6U3

Download Ideal Coordinates CCD File 
C [auth B],
D [auth C]
2-[1-[(2~{R})-2-(2-methoxyphenyl)-2-(oxan-4-yloxy)ethyl]-5-methyl-6-(1,3-oxazol-2-yl)-2,4-bis(oxidanylidene)thieno[2,3-d]pyrimidin-3-yl]-2-methyl-propanamide
C28 H32 N4 O7 S
HSRWXLIYNCKHRZ-FQEVSTJZSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 
  • Space Group: P 42 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 141.671α = 90
b = 141.671β = 90
c = 163.188γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-07-13
    Type: Initial release
  • Version 1.1: 2017-11-01
    Changes: Author supporting evidence, Database references, Derived calculations, Refinement description
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references