2WBB

FRUCTOSE-1,6-BISPHOSPHATASE(D-FRUCTOSE-1,6-BISPHOSPHATE-1- PHOSPHOHYDROLASE) (E.C.3.1.3.11) COMPLEXED WITH AN AMP SITE INHIBITOR

PDB DOI: https://doi.org/10.2210/pdb2WBB/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2009-02-26 Released: 2009-12-22
Deposition Author(s): Ruf, A., Joseph, C., Benz, J., Fol, B., Tetaz, T., Kitas, E., Mohr, P., Kuhn, B., Wessel, H.P., Hebeisen, P., Haap, W., Huber, W., Alvarez Sanchez, R., Paehler, A., Bernadeau, A., Gubler, M., Schott, B., Tozzo, E.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.22 Å
R-Value Free: 0.248
R-Value Work: 0.199
R-Value Observed: 0.202

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Sulfonylureido Thiazoles as Fructose-1,6-Bisphosphatase Inhibitors for the Treatment of Type-2 Diabetes.

Kitas, E., Mohr, P., Kuhn, B., Wessel, H.P., Hebeisen, P., Haap, W., Ruf, A., Benz, J., Joseph, C., Huber, W., Alvarez Sanchez, R., Paehler, A., Bernadeau, A., Gubler, M., Schott, B., Tozzo, E.

(2010) Bioorg Med Chem Lett 20: 594

PubMed: 19969452 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2009.11.093
Primary Citation of Related Structures:
2WBB, 2WBD

PubMed Abstract:
Sulfonylureido thiazoles were identified from a HTS campaign and optimized through a combination of structure-activity studies, X-ray crystallography and molecular modeling to yield potent inhibitors of fructose-1,6-bisphosphatase. Compound 12 showed favorable ADME properties, for example, F=70%, and a robust 32% glucose reduction in the acute db/db mouse model for Type-2 diabetes.

Organizational Affiliation

F. Hoffmann-La Roche Ltd, Discovery Research Basel, CH-4070 Basel, Switzerland. eric_a.kitas@roche.com

Macromolecule Content

Total Structure Weight: 297.89 kDa
Atom Count: 20,282
Modelled Residue Count: 2,548
Deposited Residue Count: 2,704
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
FRUCTOSE-1,6-BISPHOSPHATASE 1	A, B, C, D, E A, B, C, D, E, F, G, H	338	Homo sapiens	Mutation(s): 0 EC: 3.1.3.11
UniProt & NIH Common Fund Data Resources
Find proteins for P09467 (Homo sapiens) Explore P09467 Go to UniProtKB: P09467
PHAROS: P09467 GTEx: ENSG00000165140
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P09467
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
RO3 Query on RO3 Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain J [auth B] SDF format, chain K [auth C] SDF format, chain L [auth D] SDF format, chain M [auth E] SDF format, chain N [auth F] SDF format, chain O [auth G] SDF format, chain P [auth H] MOL2 format, chain I [auth A] MOL2 format, chain J [auth B] MOL2 format, chain K [auth C] MOL2 format, chain L [auth D] MOL2 format, chain M [auth E] MOL2 format, chain N [auth F] MOL2 format, chain O [auth G] MOL2 format, chain P [auth H]	I [auth A] J [auth B] K [auth C] L [auth D] M [auth E] I [auth A], J [auth B], K [auth C], L [auth D], M [auth E], N [auth F], O [auth G], P [auth H]	N-{[(2Z)-5-BROMO-1,3-THIAZOL-2(3H)-YLIDENE]CARBAMOYL}-4-METHYLBENZENESULFONAMIDE C₁₁ H₁₀ Br N₃ O₃ S₂ XFLQMYNYRPUILJ-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Focus chain J [auth B] Focus chain K [auth C] Focus chain L [auth D] Focus chain M [auth E] Focus chain N [auth F] Focus chain O [auth G] Focus chain P [auth H] Interactions & Density Focus chain I [auth A] Focus chain J [auth B] Focus chain K [auth C] Focus chain L [auth D] Focus chain M [auth E] Focus chain N [auth F] Focus chain O [auth G] Focus chain P [auth H]

Binding Affinity Annotations
ID	Source	Binding Affinity
RO3	PDBBind: 2WBB	IC50: 920 (nM) from 1 assay(s)
RO3	Binding MOAD: 2WBB	IC50: 920 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.22 Å
R-Value Free: 0.248
R-Value Work: 0.199
R-Value Observed: 0.202
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 64.73	α = 90
b = 278.563	β = 97.87
c = 82.702	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
XDS	data reduction
XSCALE	data scaling
MOLREP	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2009-12-22

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2009-12-22
Type: Initial release
Version 1.1: 2011-05-08
Changes: Version format compliance
Version 1.2: 2011-07-13
Changes: Version format compliance
Version 1.3: 2023-12-13
Changes: Data collection, Database references, Derived calculations, Other, Refinement description

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Help and Resources

2WBB

FRUCTOSE-1,6-BISPHOSPHATASE(D-FRUCTOSE-1,6-BISPHOSPHATE-1- PHOSPHOHYDROLASE) (E.C.3.1.3.11) COMPLEXED WITH AN AMP SITE INHIBITOR

Sulfonylureido Thiazoles as Fructose-1,6-Bisphosphatase Inhibitors for the Treatment of Type-2 Diabetes.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)