1LDY

HORSE LIVER ALCOHOL DEHYDROGENASE COMPLEXED TO NADH AND CYCLOHEXYL FORMAMIDE (CXF)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Work: 0.207 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Binding of formamides to liver alcohol dehydrogenase.

Ramaswamy, S.Scholze, M.Plapp, B.V.

(1997) Biochemistry 36: 3522-3527

  • DOI: https://doi.org/10.1021/bi962491z
  • Primary Citation of Related Structures:  
    1LDE, 1LDY

  • PubMed Abstract: 

    Amides are analogs of aldehydes and potent inhibitors of liver alcohol dehydrogenases. They can be used for structural studies and for inhibiting the metabolism of alcohols that form toxic products. We studied N-alkyl amides that bind to the enzyme-NADH complex and act as uncompetitive inhibitors against varied concentrations of ethanol (millimolar Kii values, at pH 8 and 25 degrees C): N-propylacetamide (16), delta-valerolactam (1.6), N-formylpiperidine (0.14), N-isobutylformamide (0.028), N-(cyclohexylmethyl)-formamide (0.011), and N-cyclohexylformamide (0.0087). The lower affinity of delta-valerolactam and N-propylacetamide can be explained by steric hindrance with Phe93 of the enzyme. Replacing Phe93 with Ala in the S48T/F93A mutated enzyme, which resembles the natural alpha-isoenzyme of primates, improved binding of delta-valerolactam by 210-fold. The structures of horse liver enzyme complexed with NADH and N-cyclohexylformamide or N-formylpiperidine were determined by X-ray crystallography at 2.5 A resolution. In both complexes, the carbonyl oxygens of the inhibitors bind to the catalytic zinc and form a hydrogen bond to the hydroxyl group of Ser48 of the enzyme. The six-membered rings bind in overlapping, but rotated, positions that optimize hydrophobic interactions. The binding modes of the unreactive formamides appear to resemble the Michaelis complexes of the analogous substrates, with the re face of the carbonyl carbon suitably positioned to accept a hydrogen from NADH.


  • Organizational Affiliation

    Department of Molecular Biology, Swedish University of Agricultural Sciences, Uppsala.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ALCOHOL DEHYDROGENASE
A, B, C, D
374Equus caballusMutation(s): 0 
EC: 1.1.1.1
UniProt
Find proteins for P00327 (Equus caballus)
Explore P00327 
Go to UniProtKB:  P00327
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00327
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAD
Query on NAD

Download Ideal Coordinates CCD File 
G [auth A],
K [auth B],
O [auth C],
S [auth D]
NICOTINAMIDE-ADENINE-DINUCLEOTIDE
C21 H27 N7 O14 P2
BAWFJGJZGIEFAR-NNYOXOHSSA-N
CXF
Query on CXF

Download Ideal Coordinates CCD File 
H [auth A],
L [auth B],
P [auth C],
T [auth D]
CYCLOHEXYLFORMAMIDE
C7 H13 N O
SWGXDLRCJNEEGZ-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
I [auth B]
J [auth B]
M [auth C]
E [auth A],
F [auth A],
I [auth B],
J [auth B],
M [auth C],
N [auth C],
Q [auth D],
R [auth D]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
CXF BindingDB:  1LDY Ki: min: 2300, max: 5200 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Work: 0.207 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.93α = 90
b = 180.2β = 106
c = 86.8γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata 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: 1997-04-21
    Type: Initial release
  • Version 1.1: 2008-03-24
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2024-02-14
    Changes: Data collection, Database references, Derived calculations, Other