RCSB PDB - 4BNG: Crystal structure of S. aureus FabI in complex with NADP and 5-pentyl- 2-phenoxyphenol

 4BNG

Crystal structure of S. aureus FabI in complex with NADP and 5-pentyl- 2-phenoxyphenol


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.158 

Starting Model: experimental
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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted NAPClick on this verticalbar to view detailsBest fitted 5PPClick on this verticalbar to view details

This is version 1.3 of the entry. See complete history


Literature

Rational Optimization of Drug-Target Residence Time: Insights from Inhibitor Binding to the S. Aureus Fabi Enzyme-Product Complex.

Chang, A.Schiebel, J.Yu, W.Bommineni, G.R.Pan, P.Baxter, M.V.Khanna, A.Sotriffer, C.A.Kisker, C.F.Tonge, P.J.

(2013) Biochemistry 52: 4217

  • DOI: https://doi.org/10.1021/bi400413c
  • Primary Citation of Related Structures:  
    4BNF, 4BNG, 4BNH, 4BNI, 4BNJ, 4BNK, 4BNL, 4BNM, 4BNN

  • PubMed Abstract: 

    Drug-target kinetics has recently emerged as an especially important facet of the drug discovery process. In particular, prolonged drug-target residence times may confer enhanced efficacy and selectivity in the open in vivo system. However, the lack of accurate kinetic and structural data for a series of congeneric compounds hinders the rational design of inhibitors with decreased off-rates. Therefore, we chose the Staphylococcus aureus enoyl-ACP reductase (saFabI)--an important target for the development of new anti-staphylococcal drugs--as a model system to rationalize and optimize the drug-target residence time on a structural basis. Using our new, efficient, and widely applicable mechanistically informed kinetic approach, we obtained a full characterization of saFabI inhibition by a series of 20 diphenyl ethers complemented by a collection of 9 saFabI-inhibitor crystal structures. We identified a strong correlation between the affinities of the investigated saFabI diphenyl ether inhibitors and their corresponding residence times, which can be rationalized on a structural basis. Because of its favorable interactions with the enzyme, the residence time of our most potent compound exceeds 10 h. In addition, we found that affinity and residence time in this system can be significantly enhanced by modifications predictable by a careful consideration of catalysis. Our study provides a blueprint for investigating and prolonging drug-target kinetics and may aid in the rational design of long-residence-time inhibitors targeting the essential saFabI enzyme.


  • Organizational Affiliation

    Institute for Chemical Biology & Drug Discovery, Department of Chemistry, Stony Brook University, Stony Brook, New York 11794-3400, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADPH]
A, B, C, D, E
282Staphylococcus aureus subsp. aureus N315Mutation(s): 1 
EC: 1.3.1.10 (PDB Primary Data), 1.3.1.39 (UniProt)
UniProt
Find proteins for A0A0H3JLH9 (Staphylococcus aureus (strain N315))
Explore A0A0H3JLH9 
Go to UniProtKB:  A0A0H3JLH9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A0H3JLH9
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAP
Query on NAP

Download Ideal Coordinates CCD File 
CA [auth H]
J [auth A]
L [auth B]
O [auth C]
R [auth D]
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
5PP
Query on 5PP

Download Ideal Coordinates CCD File 
BA [auth H]
I [auth A]
K [auth B]
N [auth C]
Q [auth D]
5-PENTYL-2-PHENOXYPHENOL
C17 H20 O2
OJLYTHOKCYLPMA-UHFFFAOYSA-N
GLU
Query on GLU

Download Ideal Coordinates CCD File 
AA [auth G],
M [auth B],
P [auth C],
U [auth E],
X [auth F]
GLUTAMIC ACID
C5 H9 N O4
WHUUTDBJXJRKMK-VKHMYHEASA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5PP BindingDB:  4BNG Ki: 0.04 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.158 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 89.116α = 98.56
b = 94.436β = 97.22
c = 94.88γ = 111.35
Software Package:
Software NamePurpose
REFMACrefinement
SCALAdata scaling
PHASERphasing

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 NAPClick on this verticalbar to view detailsBest fitted 5PPClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-06-05
    Type: Initial release
  • Version 1.1: 2013-07-03
    Changes: Database references
  • Version 1.2: 2017-08-09
    Changes: Data collection
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description