8DSE

Human NAMPT in complex with substrate NAM and activator quercitrin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.43 Å
  • R-Value Free: 0.183 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Mechanism of Allosteric Modulation of Nicotinamide Phosphoribosyltransferase to Elevate Cellular NAD.

Ratia, K.M.Shen, Z.Gordon-Blake, J.Lee, H.Laham, M.S.Krider, I.S.Christie, N.Ackerman-Berrier, M.Penton, C.Knowles, N.G.Musku, S.R.Fu, J.Velma, G.R.Xiong, R.Thatcher, G.R.J.

(2023) Biochemistry 62: 923-933

  • DOI: https://doi.org/10.1021/acs.biochem.2c00655
  • Primary Citation of Related Structures:  
    8DSC, 8DSD, 8DSE, 8DSH, 8DSI, 8DTJ

  • PubMed Abstract: 

    In aging and disease, cellular nicotinamide adenine dinucleotide (NAD + ) is depleted by catabolism to nicotinamide (NAM). NAD + supplementation is being pursued to enhance human healthspan and lifespan. Activation of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD + biosynthesis, has the potential to increase the salvage of NAM. Novel NAMPT-positive allosteric modulators (N-PAMs) were discovered in addition to the demonstration of NAMPT activation by biogenic phenols. The mechanism of activation was revealed through the synthesis of novel chemical probes, new NAMPT co-crystal structures, and enzyme kinetics. Binding to a rear channel in NAMPT regulates NAM binding and turnover, with biochemical observations being replicated by NAD + measurements in human cells. The mechanism of action of N-PAMs identifies, for the first time, the role of the rear channel in the regulation of NAMPT turnover coupled to productive and nonproductive NAM binding. The tight regulation of cellular NAMPT via feedback inhibition by NAM, NAD + , and adenosine 5'-triphosphate (ATP) is differentially regulated by N-PAMs and other activators, indicating that different classes of pharmacological activators may be engineered to restore or enhance NAD + levels in affected tissues.


  • Organizational Affiliation

    Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago (UIC), Chicago, Illinois 60612, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nicotinamide phosphoribosyltransferase
A, B
499Homo sapiensMutation(s): 0 
Gene Names: NAMPTPBEFPBEF1
EC: 2.4.2.12
UniProt & NIH Common Fund Data Resources
Find proteins for P43490 (Homo sapiens)
Explore P43490 
Go to UniProtKB:  P43490
PHAROS:  P43490
GTEx:  ENSG00000105835 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP43490
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
QCT (Subject of Investigation/LOI)
Query on QCT

Download Ideal Coordinates CCD File 
G [auth A],
K [auth B]
2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-oxo-4H-chromen-3-yl 6-deoxy-alpha-L-mannopyranoside
C21 H20 O11
OXGUCUVFOIWWQJ-HQBVPOQASA-N
NCA
Query on NCA

Download Ideal Coordinates CCD File 
C [auth A],
I [auth B]
NICOTINAMIDE
C6 H6 N2 O
DFPAKSUCGFBDDF-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
E [auth A],
J [auth B]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A],
F [auth A],
H [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.43 Å
  • R-Value Free: 0.183 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 60.865α = 90
b = 106.786β = 96.61
c = 82.689γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
PHENIXrefinement
MOLREPphasing
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute on Aging (NIH/NIA)United StatesRF1AG067771

Revision History  (Full details and data files)

  • Version 1.0: 2023-03-08
    Type: Initial release
  • Version 1.1: 2023-10-25
    Changes: Data collection, Refinement description