3Q7F

Cryptococcus neoformans protein farnesyltransferase in complex with FPP and ethylenediamine inhibitor 1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Structures of Cryptococcus neoformans Protein Farnesyltransferase Reveal Strategies for Developing Inhibitors That Target Fungal Pathogens.

Hast, M.A.Nichols, C.B.Armstrong, S.M.Kelly, S.M.Hellinga, H.W.Alspaugh, J.A.Beese, L.S.

(2011) J Biol Chem 286: 35149-35162

  • DOI: https://doi.org/10.1074/jbc.M111.250506
  • Primary Citation of Related Structures:  
    3Q73, 3Q75, 3Q78, 3Q79, 3Q7A, 3Q7F, 3SFX, 3SFY

  • PubMed Abstract: 

    Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals, including AIDS patients and transplant recipients. Few antifungals can treat C. neoformans infections, and drug resistance is increasing. Protein farnesyltransferase (FTase) catalyzes post-translational lipidation of key signal transduction proteins and is essential in C. neoformans. We present a multidisciplinary study validating C. neoformans FTase (CnFTase) as a drug target, showing that several anticancer FTase inhibitors with disparate scaffolds can inhibit C. neoformans and suggesting structure-based strategies for further optimization of these leads. Structural studies are an essential element for species-specific inhibitor development strategies by revealing similarities and differences between pathogen and host orthologs that can be exploited. We, therefore, present eight crystal structures of CnFTase that define the enzymatic reaction cycle, basis of ligand selection, and structurally divergent regions of the active site. Crystal structures of clinically important anticancer FTase inhibitors in complex with CnFTase reveal opportunities for optimization of selectivity for the fungal enzyme by modifying functional groups that interact with structurally diverse regions. A substrate-induced conformational change in CnFTase is observed as part of the reaction cycle, a feature that is mechanistically distinct from human FTase. Our combined structural and functional studies provide a framework for developing FTase inhibitors to treat invasive fungal infections.


  • Organizational Affiliation

    Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Farnesyltransferase alpha subunit349Cryptococcus neoformans var. grubii H99Mutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Farnesyltransferase beta subunit520Cryptococcus neoformans var. grubii H99Mutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

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Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose
C, D, E
2N/A
Glycosylation Resources
GlyTouCan:  G05551OP
GlyCosmos:  G05551OP
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ED2
Query on ED2

Download Ideal Coordinates CCD File 
L [auth B]N-benzyl-N-(2-{(4-cyanophenyl)[(1-methyl-1H-imidazol-5-yl)methyl]amino}ethyl)-1-methyl-1H-imidazole-4-sulfonamide
C25 H27 N7 O2 S
IDHGAQOVWWBGFK-UHFFFAOYSA-N
FPP
Query on FPP

Download Ideal Coordinates CCD File 
J [auth B]FARNESYL DIPHOSPHATE
C15 H28 O7 P2
VWFJDQUYCIWHTN-YFVJMOTDSA-N
3CX
Query on 3CX

Download Ideal Coordinates CCD File 
G [auth B],
H [auth B],
I [auth B]
(2S)-3-(cyclohexylamino)-2-hydroxypropane-1-sulfonic acid
C9 H19 N O4 S
INEWUCPYEUEQTN-VIFPVBQESA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
K [auth B]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
ZN
Query on ZN

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F [auth B]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 143.58α = 90
b = 143.58β = 90
c = 130.723γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-08-03
    Type: Initial release
  • Version 1.1: 2011-10-19
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2024-02-21
    Changes: Data collection, Database references, Structure summary