5Y12

Crystal structure of human FABP4 complexed with ligand 5-((4-methoxynaphthalene)-1-sulfonamido)pentanoic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.173 

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This is version 1.1 of the entry. See complete history


Literature

From hit to lead: Structure-based discovery of naphthalene-1-sulfonamide derivatives as potent and selective inhibitors of fatty acid binding protein 4

Gao, D.D.Dou, H.X.Su, H.X.Zhang, M.M.Wang, T.Liu, Q.F.Cai, H.Y.Ding, H.P.Yang, Z.Zhu, W.L.Xu, Y.C.Wang, H.Y.Li, Y.X.

(2018) Eur J Med Chem 154: 44-59

  • DOI: https://doi.org/10.1016/j.ejmech.2018.05.007
  • Primary Citation of Related Structures:  
    5Y0F, 5Y0G, 5Y0X, 5Y12, 5Y13

  • PubMed Abstract: 

    Fatty acid binding protein 4 (FABP4) plays a critical role in metabolism and inflammatory processes and therefore is a potential therapeutic target for immunometabolic diseases such as diabetes and atherosclerosis. Herein, we reported the identification of naphthalene-1-sulfonamide derivatives as novel, potent and selective FABP4 inhibitors by applying a structure-based design strategy. The binding affinities of compounds 16dk, 16do and 16du to FABP4, at the molecular level, are equivalent to or even better than that of BMS309403. The X-ray crystallography complemented by the isothermal titration calorimetry studies revealed the binding mode of this series of inhibitors and the pivotal network of ordered water molecules in the binding pocket of FABP4. Moreover, compounds 16dk and 16do showed good metabolic stabilities in liver microsomes. Further extensive in vivo study demonstrated that 16dk and 16do exhibited a dramatic improvement in glucose and lipid metabolism, by decreasing fasting blood glucose and serum lipid levels, enhancing insulin sensitivity, and ameliorating hepatic steatosis in obese diabetic (db/db) mice.


  • Organizational Affiliation

    School of Pharmacy, Fudan University, Shanghai 201203, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fatty acid-binding protein, adipocyte152Homo sapiensMutation(s): 0 
Gene Names: FABP4
UniProt & NIH Common Fund Data Resources
Find proteins for P15090 (Homo sapiens)
Explore P15090 
Go to UniProtKB:  P15090
PHAROS:  P15090
GTEx:  ENSG00000170323 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP15090
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8JX (Subject of Investigation/LOI)
Query on 8JX

Download Ideal Coordinates CCD File 
B [auth A]5-[(4-methoxynaphthalen-1-yl)sulfonylamino]pentanoic acid
C16 H19 N O5 S
ZPHHWDJVJHTZHN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
8JX BindingDB:  5Y12 Ki: 590 (nM) from 1 assay(s)
Binding MOAD:  5Y12 Ki: 590 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.173 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 32.56α = 90
b = 53.61β = 90
c = 75.42γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
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: 2018-06-06
    Type: Initial release
  • Version 1.1: 2024-03-27
    Changes: Data collection, Database references