1HNN

CRYSTAL STRUCTURE OF HUMAN PNMT COMPLEXED WITH SK&F 29661 AND ADOHCY(SAH)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.232 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Getting the adrenaline going: crystal structure of the adrenaline-synthesizing enzyme PNMT.

Martin, J.L.Begun, J.McLeish, M.J.Caine, J.M.Grunewald, G.L.

(2001) Structure 9: 977-985

  • DOI: https://doi.org/10.1016/s0969-2126(01)00662-1
  • Primary Citation of Related Structures:  
    1HNN

  • PubMed Abstract: 

    Adrenaline is localized to specific regions of the central nervous system (CNS), but its role therein is unclear because of a lack of suitable pharmacologic agents. Ideally, a chemical is required that crosses the blood-brain barrier, potently inhibits the adrenaline-synthesizing enzyme PNMT, and does not affect other catecholamine processes. Currently available PNMT inhibitors do not meet these criteria. We aim to produce potent, selective, and CNS-active PNMT inhibitors by structure-based design methods. The first step is the structure determination of PNMT. We have solved the crystal structure of human PNMT complexed with a cofactor product and a submicromolar inhibitor at a resolution of 2.4 A. The structure reveals a highly decorated methyltransferase fold, with an active site protected from solvent by an extensive cover formed from several discrete structural motifs. The structure of PNMT shows that the inhibitor interacts with the enzyme in a different mode from the (modeled) substrate noradrenaline. Specifically, the position and orientation of the amines is not equivalent. An unexpected finding is that the structure of PNMT provides independent evidence of both backward evolution and fold recruitment in the evolution of a complex enzyme from a simple fold. The proposed evolutionary pathway implies that adrenaline, the product of PNMT catalysis, is a relative newcomer in the catecholamine family. The PNMT structure reported here enables the design of potent and selective inhibitors with which to characterize the role of adrenaline in the CNS. Such chemical probes could potentially be useful as novel therapeutics.


  • Organizational Affiliation

    Centre for Drug Design and Development and Special Research Centre for Functional and Applied Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PHENYLETHANOLAMINE N-METHYLTRANSFERASE
A, B
282Homo sapiensMutation(s): 0 
Gene Names: PNMT
EC: 2.1.1.28
UniProt & NIH Common Fund Data Resources
Find proteins for P11086 (Homo sapiens)
Explore P11086 
Go to UniProtKB:  P11086
PHAROS:  P11086
GTEx:  ENSG00000141744 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11086
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
SKF BindingDB:  1HNN Ki: min: 120, max: 2840 (nM) from 4 assay(s)
PDBBind:  1HNN Ki: 580 (nM) from 1 assay(s)
SAH BindingDB:  1HNN Ki: 1.40e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.232 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.35α = 90
b = 94.35β = 90
c = 187.7γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
SHARPphasing
CNSrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2001-12-07
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2024-02-07
    Changes: Data collection, Database references, Derived calculations