5YJI

Co-crystal structure of Mouse Nicotinamide N-methyltransferase (NNMT) with small molecule analog of Nicotinamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.212 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

A small molecule inhibitor of Nicotinamide N-methyltransferase for the treatment of metabolic disorders.

Kannt, A.Rajagopal, S.Kadnur, S.V.Suresh, J.Bhamidipati, R.K.Swaminathan, S.Hallur, M.S.Kristam, R.Elvert, R.Czech, J.Pfenninger, A.Rudolph, C.Schreuder, H.Chandrasekar, D.V.Mane, V.S.Birudukota, S.Shaik, S.Zope, B.R.Burri, R.R.Anand, N.N.Thakur, M.K.Singh, M.Parveen, R.Kandan, S.Mullangi, R.Yura, T.Gosu, R.Ruf, S.Dhakshinamoorthy, S.

(2018) Sci Rep 8: 3660-3660

  • DOI: https://doi.org/10.1038/s41598-018-22081-7
  • Primary Citation of Related Structures:  
    5YJF, 5YJI

  • PubMed Abstract: 

    Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from the co-factor S-adenosyl-L-methionine (SAM) onto the substrate, nicotinamide (NA) to form 1-methyl-nicotinamide (MNA). Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes. Here we report a small molecule analog of NA, JBSNF-000088, that inhibits NNMT activity, reduces MNA levels and drives insulin sensitization, glucose modulation and body weight reduction in animal models of metabolic disease. In mice with high fat diet (HFD)-induced obesity, JBSNF-000088 treatment caused a reduction in body weight, improved insulin sensitivity and normalized glucose tolerance to the level of lean control mice. These effects were not seen in NNMT knockout mice on HFD, confirming specificity of JBSNF-000088. The compound also improved glucose handling in ob/ob and db/db mice albeit to a lesser extent and in the absence of weight loss. Co-crystal structure analysis revealed the presence of the N-methylated product of JBSNF-000088 bound to the NNMT protein. The N-methylated product was also detected in the plasma of mice treated with JBSNF-000088. Hence, JBSNF-000088 may act as a slow-turnover substrate analog, driving the observed metabolic benefits.


  • Organizational Affiliation

    Sanofi Research and Development, Industriepark Hoechst, H823, D-65926, Frankfurt am Main, Germany. aimo.kannt@sanofi.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nicotinamide N-methyltransferase
A, B
284Mus musculusMutation(s): 0 
Gene Names: Nnmt
EC: 2.1.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for O55239 (Mus musculus)
Explore O55239 
Go to UniProtKB:  O55239
IMPC:  MGI:1099443
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO55239
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
8WO Binding MOAD:  5YJI IC50: 5000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.210 
  • R-Value Observed: 0.212 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.356α = 90
b = 71.622β = 90
c = 157.408γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2018-03-21
    Type: Initial release
  • Version 1.1: 2023-11-22
    Changes: Data collection, Database references, Refinement description