7SVT | pdb_00007svt

Mycobacterium tuberculosis 3-hydroxyl-ACP dehydratase HadAB in complex with 1,3-diarylpyrazolyl-acylsulfonamide inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 
    0.275 (Depositor), 0.270 (DCC) 
  • R-Value Work: 
    0.217 (Depositor), 0.220 (DCC) 
  • R-Value Observed: 
    0.220 (Depositor) 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted CI7Click on this verticalbar to view details

This is version 1.2 of the entry. See complete history


Literature

1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in Mycobacterium tuberculosis .

Singh, V.Grzegorzewicz, A.E.Fienberg, S.Muller, R.Khonde, L.P.Sanz, O.Alfonso, S.Urones, B.Drewes, G.Bantscheff, M.Ghidelli-Disse, S.Ioerger, T.R.Angala, B.Liu, J.Lee, R.E.Sacchettini, J.C.Krieger, I.V.Jackson, M.Chibale, K.Ghorpade, S.R.

(2022) ACS Infect Dis 8: 2315-2326

  • DOI: https://doi.org/10.1021/acsinfecdis.2c00392
  • Primary Citation of Related Structures:  
    7SVT

  • PubMed Abstract: 

    Alternative mode-of-inhibition of clinically validated targets is an effective strategy for circumventing existing clinical drug resistance. Herein, we report 1,3-diarylpyrazolyl-acylsulfonamides as potent inhibitors of HadAB/BC, a 3-hydroxyl-ACP dehydratase complex required to iteratively elongate the meromycolate chain of mycolic acids in Mycobacterium tuberculosis ( Mtb ). Mutations in compound 1 -resistant Mtb mutants mapped to HadC (Rv0637; K157R), while chemoproteomics confirmed the compound's binding to HadA (Rv0635), HadB (Rv0636), and HadC. The compounds effectively inhibited the HadAB and HadBC enzyme activities and affected mycolic acid biosynthesis in Mtb , in a concentration-dependent manner. Unlike known 3-hydroxyl-ACP dehydratase complex inhibitors of clinical significance, isoxyl and thioacetazone, 1,3-diarylpyrazolyl-acylsulfonamides did not require activation by EthA and thus are not liable to EthA-mediated resistance. Further, the crystal structure of a key compound in a complex with Mtb HadAB revealed unique binding interactions within the active site of HadAB, providing a useful tool for further structure-based optimization of the series.


  • Organizational Affiliation

    Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch7701, South Africa.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HadAA,
C [auth H],
E [auth O],
G [auth V]
158Mycobacterium tuberculosisMutation(s): 0 
UniProt
Find proteins for P9WFK1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WFK1 
Go to UniProtKB:  P9WFK1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WFK1
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
(3R)-hydroxyacyl-ACP dehydratase subunit HadBB,
D [auth I],
F [auth P],
H [auth W]
142Mycobacterium tuberculosisMutation(s): 0 
EC: 4.2.1
UniProt
Find proteins for I6WYY7 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore I6WYY7 
Go to UniProtKB:  I6WYY7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupI6WYY7
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CI7 (Subject of Investigation/LOI)
Query on CI7

Download Ideal Coordinates CCD File 
I [auth A],
K [auth H],
L [auth O],
P [auth V]
3-[1-(4-bromophenyl)-3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-(methanesulfonyl)propanamide
C19 H17 Br Cl N3 O3 S
HJRIVXBUFBERIX-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
M [auth O],
N [auth O]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
O
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
J [auth B],
Q [auth V]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free:  0.275 (Depositor), 0.270 (DCC) 
  • R-Value Work:  0.217 (Depositor), 0.220 (DCC) 
  • R-Value Observed: 0.220 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.298α = 90
b = 107.197β = 90
c = 142.066γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted CI7Click on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2022-11-16
    Type: Initial release
  • Version 1.1: 2022-11-23
    Changes: Database references
  • Version 1.2: 2023-10-18
    Changes: Data collection, Refinement description