1U3W

Crystal Structure of Human Alcohol Dehydrogenase Gamma-2-Gamma-2 Isoform Complexed with N-1-Methylheptylformamide Determined to 1.45 Angstrom Resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.185 

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This is version 1.4 of the entry. See complete history


Literature

Structure of three class I human alcohol dehydrogenases complexed with isoenzyme specific formamide inhibitors

Gibbons, B.J.Hurley, T.D.

(2004) Biochemistry 43: 12555-12562

  • DOI: https://doi.org/10.1021/bi0489107
  • Primary Citation of Related Structures:  
    1U3T, 1U3U, 1U3V, 1U3W

  • PubMed Abstract: 

    Formamides are aldehyde analogues that have demonstrated potent and selective inhibition of human alcohol dehydrogenase isoenzymes. The alphaalpha, beta(1)beta(1), gamma(2)gamma(2), and sigmasigma isoforms have all been found to be strongly inhibited by substituted formamides. In this paper, the structure of the alphaalpha isoform of human alcohol dehydrogenase complexed with N-cyclopentyl-N-cyclobutylformamide was determined by X-ray crystallography to 2.5 A resolution, the beta(1)beta(1) isoform of human alcohol dehydrogenase complexed with N-benzylformamide and with N-heptylformamide was determined to 1.6 and 1.65 A resolution, respectively, and the structure of the gamma(2)gamma(2) isoform complexed with N-1-methylheptylformamide was determined to 1.45 A resolution. These structures provide the first substrate-level view of the local structural differences that give rise to the individual substrate preferences shown by these highly related isoenzymes. Consistent with previous work, the carbonyl oxygen of the inhibitors interacts directly with the catalytic zinc and the hydroxyl group of Thr48 (Ser48 for gamma(2)gamma(2)) of the enzyme. The benzene ring of N-benzylformamide and the carbon chains of N-heptylformamide and N-1-methylheptylformamide interact with the sides of the hydrophobic substrate pocket whose size and shape is dictated by residue exchanges between the beta(1)beta(1) and gamma(2)gamma(2) isoenzymes. In particular, the exchange of Ser for Thr at position 48 and the exchange of Val for Leu at position 141 in the gamma(2)gamma(2) isoenzyme create an environment with stereoselectivity for the R-enantiomer of the branched N-1-methylheptylformamide inhibitor in this isoenzyme. The primary feature of the alphaalpha isoform is the Ala for Phe93 exchange that enlarges the active site near the catalytic zinc and creates the specificity for the branched N-cyclopentyl-N-cyclobutylformamide inhibitor, which shows the greatest selectivity for this unique isoenzyme of any of the formamide inhibitors.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Room MS 4017, Indianapolis, Indiana 46202-5122, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Alcohol dehydrogenase gamma chain
A, B
374Homo sapiensMutation(s): 0 
Gene Names: ADH1C
EC: 1.1.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00326 (Homo sapiens)
Explore P00326 
Go to UniProtKB:  P00326
PHAROS:  P00326
GTEx:  ENSG00000248144 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00326
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 
E [auth A],
I [auth B]
NICOTINAMIDE-ADENINE-DINUCLEOTIDE
C21 H27 N7 O14 P2
BAWFJGJZGIEFAR-NNYOXOHSSA-N
FXY
Query on FXY

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B]
1-METHYLHEPTYLFORMAMIDE
C9 H19 N O
YWFHDUFNGSJLTL-SECBINFHSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
G [auth B],
H [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FXY BindingDB:  1U3W Ki: min: 410, max: 7000 (nM) from 3 assay(s)
Binding MOAD:  1U3W Ki: 410 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.185 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.361α = 90
b = 67.125β = 103.75
c = 92.725γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
CCP4data scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-10-26
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 1.4: 2023-10-25
    Changes: Data collection, Database references, Derived calculations, Refinement description