6EZM

Imidazoleglycerol-phosphate dehydratase from Saccharomyces cerevisiae


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.20 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Elucidating the structural basis for differing enzyme inhibitor potency by cryo-EM.

Rawson, S.Bisson, C.Hurdiss, D.L.Fazal, A.McPhillie, M.J.Sedelnikova, S.E.Baker, P.J.Rice, D.W.Muench, S.P.

(2018) Proc Natl Acad Sci U S A 115: 1795-1800

  • DOI: https://doi.org/10.1073/pnas.1708839115
  • Primary Citation of Related Structures:  
    6EZJ, 6EZM

  • PubMed Abstract: 

    Histidine biosynthesis is an essential process in plants and microorganisms, making it an attractive target for the development of herbicides and antibacterial agents. Imidazoleglycerol-phosphate dehydratase (IGPD), a key enzyme within this pathway, has been biochemically characterized in both Saccharomyces cerevisiae ( Sc_ IGPD) and Arabidopsis thaliana ( At_ IGPD). The plant enzyme, having been the focus of in-depth structural analysis as part of an inhibitor development program, has revealed details about the reaction mechanism of IGPD, whereas the yeast enzyme has proven intractable to crystallography studies. The structure-activity relationship of potent triazole-phosphonate inhibitors of IGPD has been determined in both homologs, revealing that the lead inhibitor (C348) is an order of magnitude more potent against Sc_ IGPD than At_ IGPD; however, the molecular basis of this difference has not been established. Here we have used single-particle electron microscopy (EM) to study structural differences between the At and Sc_ IGPD homologs, which could influence the difference in inhibitor potency. The resulting EM maps at ∼3 Å are sufficient to de novo build the protein structure and identify the inhibitor binding site, which has been validated against the crystal structure of the At_ IGPD/C348 complex. The structure of Sc _IGPD reveals that a 24-amino acid insertion forms an extended loop region on the enzyme surface that lies adjacent to the active site, forming interactions with the substrate/inhibitor binding loop that may influence inhibitor potency. Overall, this study provides insights into the IGPD family and demonstrates the power of using an EM approach to study inhibitor binding.


  • Organizational Affiliation

    School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT Leeds, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Imidazoleglycerol-phosphate dehydratase220Saccharomyces cerevisiae S288CMutation(s): 0 
Gene Names: HIS3YOR202W
EC: 4.2.1.19
UniProt
Find proteins for P06633 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c))
Explore P06633 
Go to UniProtKB:  P06633
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06633
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5LD (Subject of Investigation/LOI)
Query on 5LD

Download Ideal Coordinates CCD File 
AA [auth U]
AB [auth E]
CC [auth K]
DA [auth U]
EB [auth E]
AA [auth U],
AB [auth E],
CC [auth K],
DA [auth U],
EB [auth E],
EC [auth K],
FA [auth A],
HB [auth F],
HC [auth M],
JA [auth A],
JB [auth G],
LB [auth G],
LC [auth M],
MA [auth B],
OA [auth B],
OC [auth O],
PB [auth H],
QC [auth O],
SA [auth C],
SB [auth I],
UA [auth C],
WB [auth I],
XA [auth D],
ZB [auth J]
[(2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]phosphonic acid
C5 H10 N3 O4 P
ZXKJPBBOMRHTCH-RXMQYKEDSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
AC [auth K]
BA [auth U]
BB [auth E]
BC [auth K]
CA [auth U]
AC [auth K],
BA [auth U],
BB [auth E],
BC [auth K],
CA [auth U],
CB [auth E],
DB [auth E],
DC [auth K],
EA [auth A],
FB [auth F],
FC [auth K],
GA [auth A],
GB [auth F],
GC [auth M],
HA [auth A],
IA [auth A],
IB [auth G],
IC [auth M],
JC [auth M],
KA [auth B],
KB [auth G],
KC [auth M],
LA [auth B],
MB [auth G],
MC [auth O],
NA [auth B],
NB [auth G],
NC [auth O],
OB [auth H],
PA [auth B],
PC [auth O],
QA [auth C],
QB [auth H],
RA [auth C],
RB [auth I],
RC [auth O],
TA [auth C],
TB [auth I],
UB [auth I],
VA [auth C],
VB [auth I],
WA [auth D],
XB [auth J],
Y [auth U],
YA [auth D],
YB [auth J],
Z [auth U],
ZA [auth E]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.20 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
MODEL REFINEMENTPHENIX
RECONSTRUCTIONRELION

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Wellcome TrustUnited Kingdom(009752/Z/12/Z) and (102572/B/13/Z)
Biotechnology and Biological Sciences Research CouncilUnited KingdomBB/I003703/1
Medical Research Council (United Kingdom)United KingdomG100567

Revision History  (Full details and data files)

  • Version 1.0: 2018-02-07
    Type: Initial release
  • Version 1.1: 2018-02-21
    Changes: Database references
  • Version 1.2: 2018-02-28
    Changes: Database references
  • Version 1.3: 2019-12-11
    Changes: Other