3ROQ

Crystal structure of human CD38 in complex with compound CZ-46


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Catalysis-based inhibitors of the calcium signaling function of CD38.

Kwong, A.K.Chen, Z.Zhang, H.Leung, F.P.Lam, C.M.Ting, K.Y.Zhang, L.Hao, Q.Zhang, L.H.Lee, H.C.

(2012) Biochemistry 51: 555-564

  • DOI: https://doi.org/10.1021/bi201509f
  • Primary Citation of Related Structures:  
    3ROK, 3ROM, 3ROP, 3ROQ

  • PubMed Abstract: 

    CD38 is a signaling enzyme responsible for catalyzing the synthesis of cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate; both are universal Ca(2+) messenger molecules. Ablation of the CD38 gene in mice causes multiple physiological defects, including impaired oxytocin release, that result in altered social behavior. A series of catalysis-based inhibitors of CD38 were designed and synthesized, starting with arabinosyl-2'-fluoro-2'-deoxynicotinamide mononucleotide. Structure-function relationships were analyzed to assess the structural determinants important for inhibiting the NADase activity of CD38. X-ray crystallography was used to reveal the covalent intermediates that were formed with the catalytic residue, Glu226. Metabolically stable analogues that were resistant to inactivation by phosphatase and esterase were synthesized and shown to be effective in inhibiting intracellular cADPR production in human HL-60 cells during induction of differentiation by retinoic acid. The inhibition was species-independent, and the analogues were similarly effective in blocking the cyclization reaction of CD38 in rat ventricular tissue extracts, as well as inhibiting the α-agonist-induced constriction in rat mesentery arteries. These compounds thus represent the first generally applicable and catalysis-based inhibitors of the Ca(2+) signaling function of CD38.


  • Organizational Affiliation

    Department of Physiology, 4/F Lab Block, University of Hong Kong, Hong Kong.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ADP-ribosyl cyclase 1
A, B
254Homo sapiensMutation(s): 4 
Gene Names: CD38
EC: 3.2.2.5
UniProt & NIH Common Fund Data Resources
Find proteins for P28907 (Homo sapiens)
Explore P28907 
Go to UniProtKB:  P28907
PHAROS:  P28907
GTEx:  ENSG00000004468 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28907
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
46Z
Query on 46Z

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(2R,3R,4S,5S)-4-fluoro-3,5-dihydroxytetrahydrofuran-2-yl 2-phenylethyl hydrogen (S)-phosphate
C12 H16 F O7 P
SMTSAPKONQAWEG-FIQHERPVSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.881α = 109.33
b = 53.511β = 90.53
c = 63.906γ = 94.83
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
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: 2011-12-21
    Type: Initial release
  • Version 1.1: 2013-07-03
    Changes: Database references, Non-polymer description
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Database references, Derived calculations
  • Version 1.4: 2023-11-01
    Changes: Data collection, Database references, Refinement description