5IBF

Crystal structure Mycobacterium tuberculosis CYP121 in complex with inhibitor fragment 19a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors.

Kavanagh, M.E.Coyne, A.G.McLean, K.J.James, G.G.Levy, C.W.Marino, L.B.de Carvalho, L.P.Chan, D.S.Hudson, S.A.Surade, S.Leys, D.Munro, A.W.Abell, C.

(2016) J Med Chem 59: 3272-3302

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00007
  • Primary Citation of Related Structures:  
    5EDT, 5IBD, 5IBE, 5IBF, 5IBG, 5IBH, 5IBI, 5IBJ

  • PubMed Abstract: 

    The essential enzyme CYP121 is a target for drug development against antibiotic resistant strains of Mycobacterium tuberculosis. A triazol-1-yl phenol fragment 1 was identified to bind to CYP121 using a cascade of biophysical assays. Synthetic merging and optimization of 1 produced a 100-fold improvement in binding affinity, yielding lead compound 2 (KD = 15 μM). Deconstruction of 2 into its component retrofragments allowed the group efficiency of structural motifs to be assessed, the identification of more LE scaffolds for optimization and highlighted binding affinity hotspots. Structure-guided addition of a metal-binding pharmacophore onto LE retrofragment scaffolds produced low nanomolar (KD = 15 nM) CYP121 ligands. Elaboration of these compounds to target binding hotspots in the distal active site afforded compounds with excellent selectivity against human drug-metabolizing P450s. Analysis of the factors governing ligand potency and selectivity using X-ray crystallography, UV-vis spectroscopy, and native mass spectrometry provides insight for subsequent drug development.


  • Organizational Affiliation

    Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mycocyclosin synthase396Mycobacterium tuberculosisMutation(s): 0 
Gene Names: cyp121MT2336
EC: 1.14.21.9
UniProt
Find proteins for P9WPP7 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WPP7 
Go to UniProtKB:  P9WPP7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WPP7
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
69W Binding MOAD:  5IBF Kd: 1.40e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.097α = 90
b = 78.097β = 90
c = 265.553γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
xia2data reduction
xia2data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-04-06 
  • Deposition Author(s): Levy, C.

Revision History  (Full details and data files)

  • Version 1.0: 2016-04-06
    Type: Initial release
  • Version 1.1: 2016-04-27
    Changes: Database references
  • Version 1.2: 2019-10-16
    Changes: Data collection