3EWX

K314A mutant of human orotidyl-5'-monophosphate decarboxylase in complex with 6-azido-UMP, degraded to BMP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.178 
  • R-Value Work: 0.150 
  • R-Value Observed: 0.152 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Lys314 is a nucleophile in non-classical reactions of orotidine-5'-monophosphate decarboxylase

Heinrich, D.Diederichsen, U.Rudolph, M.G.

(2009) Chemistry 15: 6619-6625

  • DOI: https://doi.org/10.1002/chem.200900397
  • Primary Citation of Related Structures:  
    3EWU, 3EWW, 3EWX, 3EWY, 3EWZ, 3EX1, 3EX2, 3EX3, 3EX4, 3EX6, 3L0K, 3L0N

  • PubMed Abstract: 

    Orotidine-5'-monophosphate decarboxylase (OMPD) catalyzes the decarboxylation of orotidine-5'-monophosphate (OMP) to uridine-5'-monophosphate (UMP) in an extremely proficient manner. The reaction does not require any cofactors and proceeds by an unknown mechanism. In addition to decarboxylation, OMPD is able to catalyze other reactions. We show that several C6-substituted UMP derivatives undergo hydrolysis or substitution reactions that depend on a lysine residue (Lys314) in the OMPD active site. 6-Cyano-UMP is converted to UMP, and UMP derivatives with good leaving groups inhibit OMPD by a suicide mechanism in which Lys314 covalently binds to the substrate. These non-classical reactivities of human OMPD were characterized by cocrystallization and freeze-trapping experiments with wild-type OMPD and two active-site mutants by using substrate and inhibitor nucleotides. The structures show that the C6-substituents are not coplanar with the pyrimidine ring. The extent of this substrate distortion is a function of the substituent geometry. Structure-based mechanisms for the reaction of 6-substituted UMP derivatives are extracted in accordance with results from mutagenesis, mass spectrometry, and OMPD enzyme activity. The Lys314-based mechanisms explain the chemodiversity of OMPD, and offer a strategy to design mechanism-based inhibitors that could be used for antineoplastic purposes for example.


  • Organizational Affiliation

    Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Orotidine-5'-phosphate decarboxylase260Homo sapiensMutation(s): 1 
Gene Names: UMPS
EC: 4.1.1.23
UniProt & NIH Common Fund Data Resources
Find proteins for P11172 (Homo sapiens)
Explore P11172 
Go to UniProtKB:  P11172
PHAROS:  P11172
GTEx:  ENSG00000114491 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11172
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BMP
Query on BMP

Download Ideal Coordinates CCD File 
B [auth A]6-HYDROXYURIDINE-5'-PHOSPHATE
C9 H13 N2 O10 P
UDOBICLZEKUKCV-YXZULKJRSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.178 
  • R-Value Work: 0.150 
  • R-Value Observed: 0.152 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.75α = 90
b = 116.72β = 90
c = 61.8γ = 90
Software Package:
Software NamePurpose
COMOphasing
REFMACrefinement
XDSdata reduction
SADABSdata 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: 2009-04-07
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Refinement description
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-12-27
    Changes: Data collection