4EA0

Crystal structure of dehydrosqualene synthase (Crtm) from S. aureus complexed with diphosphate and quinuclidine BPH-651

PDB DOI: https://doi.org/10.2210/pdb4EA0/pdb

Classification: TRANSFERASE/TRANSFERASE INHIBITOR
Organism(s): Staphylococcus aureus
Expression System: Escherichia coli BL21
Mutation(s): No

Deposited: 2012-03-21 Released: 2012-04-25
Deposition Author(s): Lin, F.-Y., Liu, Y.-L., Oldfield, E.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.12 Å
R-Value Free: 0.278
R-Value Work: 0.222
R-Value Observed: 0.225

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Head-to-Head Prenyl Tranferases: Anti-Infective Drug Targets.

Lin, F.Y., Liu, Y.L., Li, K., Cao, R., Zhu, W., Axelson, J., Pang, R., Oldfield, E.

(2012) J Med Chem 55: 4367-4372

PubMed: 22486710 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/jm300208p
Primary Citation of Related Structures:
4E9U, 4E9Z, 4EA0, 4EA1, 4EA2

PubMed Abstract:
We report X-ray crystallographic structures of three inhibitors bound to dehydrosqualene synthase from Staphylococcus aureus: 1 (BPH-651), 2 (WC-9), and 3 (SQ-109). Compound 2 binds to the S2 site with its -SCN group surrounded by four hydrogen bond donors. With 1, we report two structures: in both, the quinuclidine headgroup binds in the allylic (S1) site with the side chain in S2, but in the presence of PPi and Mg(2+), the quinuclidine's cationic center interacts with PPi and three Mg(2+), mimicking a transition state involved in diphosphate ionization. With 3, there are again two structures. In one, the geranyl side chain binds to either S1 or S2 and the adamantane headgroup binds to S1. In the second, the side chain binds to S2 while the headgroup binds to S1. These results provide structural clues for the mechanism and inhibition of the head-to-head prenyl transferases and should aid future drug design.

Organizational Affiliation

Center for Biophysics and Computational Biology,University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.

Macromolecule Content

Total Structure Weight: 69.93 kDa
Atom Count: 5,046
Modelled Residue Count: 568
Deposited Residue Count: 574
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Dehydrosqualene synthase	A, B	287	Staphylococcus aureus	Mutation(s): 0 Gene Names: crtM EC: 2.5.1.96
UniProt
Find proteins for A9JQL9 (Staphylococcus aureus) Explore A9JQL9 Go to UniProtKB: A9JQL9
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	A9JQL9
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
651 Query on 651 Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain M [auth B] MOL2 format, chain H [auth A] MOL2 format, chain M [auth B]	H [auth A], M [auth B]	(3R)-3-biphenyl-4-yl-1-azabicyclo[2.2.2]octan-3-ol C₁₉ H₂₁ N O WPCQYFUQHBLGAX-IBGZPJMESA-N		Interactions Focus chain H [auth A] Focus chain M [auth B] Interactions & Density Focus chain H [auth A] Focus chain M [auth B]
POP Query on POP Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain L [auth B] MOL2 format, chain F [auth A] MOL2 format, chain L [auth B]	F [auth A], L [auth B]	PYROPHOSPHATE 2- H₂ O₇ P₂ XPPKVPWEQAFLFU-UHFFFAOYSA-L		Interactions Focus chain F [auth A] Focus chain L [auth B] Interactions & Density Focus chain F [auth A] Focus chain L [auth B]
TLA Query on TLA Download Ideal Coordinates CCD File SDF format, chain G [auth A] MOL2 format, chain G [auth A]	G [auth A]	L(+)-TARTARIC ACID C₄ H₆ O₆ FEWJPZIEWOKRBE-JCYAYHJZSA-N		Interactions Focus chain G [auth A] Interactions & Density Focus chain G [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain K [auth B] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B]	C [auth A] D [auth A] E [auth A] I [auth B] J [auth B] C [auth A], D [auth A], E [auth A], I [auth B], J [auth B], K [auth B]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain E [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.12 Å
R-Value Free: 0.278
R-Value Work: 0.222
R-Value Observed: 0.225
Space Group: P 3₁ 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 80.324	α = 90
b = 80.324	β = 90
c = 180.822	γ = 120

Software Package:

Software Name	Purpose
PHASES	phasing
REFMAC	refinement
HKL-2000	data reduction
HKL-2000	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2012-04-25

Deposition Author(s):

Lin, F.-Y.

Liu, Y.-L.

Oldfield, E.

Revision History (Full details and data files)

Version 1.0: 2012-04-25
Type: Initial release
Version 1.1: 2012-05-16
Changes: Database references
Version 1.2: 2024-02-28
Changes: Data collection, Database references, Derived calculations