5FIC

Open form of murine Acid Sphingomyelinase in presence of lipid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Crystal structure of mammalian acid sphingomyelinase.

Gorelik, A.Illes, K.Heinz, L.X.Superti-Furga, G.Nagar, B.

(2016) Nat Commun 7: 12196-12196

  • DOI: https://doi.org/10.1038/ncomms12196
  • Primary Citation of Related Structures:  
    5FI9, 5FIB, 5FIC, 5HQN

  • PubMed Abstract: 

    Acid sphingomyelinase (ASMase, ASM, SMPD1) converts sphingomyelin into ceramide, modulating membrane properties and signal transduction. Inactivating mutations in ASMase cause Niemann-Pick disease, and its inhibition is also beneficial in models of depression and cancer. To gain a better understanding of this critical therapeutic target, we determined crystal structures of mammalian ASMase in various conformations. The catalytic domain adopts a calcineurin-like fold with two zinc ions and a hydrophobic track leading to the active site. Strikingly, the membrane interacting saposin domain assumes either a closed globular conformation independent from the catalytic domain, or an open conformation, which establishes an interface with the catalytic domain essential for activity. Structural mapping of Niemann-Pick mutations reveals that most of them likely destabilize the protein's fold. This study sheds light on the molecular mechanism of ASMase function, and provides a platform for the rational development of ASMase inhibitors and therapeutic use of recombinant ASMase.


  • Organizational Affiliation

    Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 0B1.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Sphingomyelin phosphodiesterase
A, B, C, D
538Mus musculusMutation(s): 0 
Gene Names: Smpd1Asm
EC: 3.1.4.12
Membrane Entity: Yes 
UniProt
Find proteins for Q04519 (Mus musculus)
Explore Q04519 
Go to UniProtKB:  Q04519
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ04519
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
E, I
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G15407YE
GlyCosmos:  G15407YE
GlyGen:  G15407YE
Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose
F, J
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G21290RB
GlyCosmos:  G21290RB
GlyGen:  G21290RB
Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
G, H
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6E0
Query on 6E0

Download Ideal Coordinates CCD File 
HA [auth D],
R [auth A]
octadecylphosphonic acid
C18 H39 O3 P
FTMKAMVLFVRZQX-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
AA [auth C],
U [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
BA [auth C]
FA [auth D]
M [auth A]
N [auth A]
O [auth A]
BA [auth C],
FA [auth D],
M [auth A],
N [auth A],
O [auth A],
V [auth B],
W [auth B]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
ZN
Query on ZN

Download Ideal Coordinates CCD File 
DA [auth D]
EA [auth D]
K [auth A]
L [auth A]
S [auth B]
DA [auth D],
EA [auth D],
K [auth A],
L [auth A],
S [auth B],
T [auth B],
Y [auth C],
Z [auth C]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
CA [auth C],
GA [auth D],
P [auth A],
Q [auth A],
X [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 101.75α = 90
b = 101.75β = 90
c = 401.83γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-07-06
    Type: Initial release
  • Version 1.1: 2016-08-03
    Changes: Database references
  • Version 1.2: 2018-06-20
    Changes: Data collection, Derived calculations, Structure summary
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary