4JYV

Structure of factor VIIA in complex with the inhibitor (2R)-2-[3-ETHOXY-4-(PROPAN-2-YLOXY)PHENYL]-2-(ISOQUINOLIN-6-YLAMINO)-N-[(3-SULFAMOYLPHENYL)SULFONYL]ETHANAMIDE

PDB DOI: https://doi.org/10.2210/pdb4JYV/pdb

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Cricetinae
Mutation(s): No

Deposited: 2013-04-01 Released: 2013-07-24
Deposition Author(s): Wei, A., Anumula, R.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.19 Å
R-Value Free: 0.215
R-Value Work: 0.196
R-Value Observed: 0.197

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Nonbenzamidine acylsulfonamide tissue factor-factor VIIa inhibitors.

Glunz, P.W., Zhang, X., Zou, Y., Delucca, I., Nirschl, A.H., Cheng, X., Weigelt, C.A., Cheney, D.L., Wei, A., Anumula, R., Luettgen, J.M., Rendina, A.R., Harpel, M., Luo, G., Knabb, R., Wong, P.C., Wexler, R.R., Priestley, E.S.

(2013) Bioorg Med Chem Lett 23: 5244-5248

PubMed: 23845220 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2013.06.027
Primary Citation of Related Structures:
4JYU, 4JYV

PubMed Abstract:
Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P' binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype.

Organizational Affiliation

Bristol-Myers Squibb R&D, Pennington, NJ 08534, United States. peter.glunz@bms.com

Macromolecule Content

Total Structure Weight: 35.53 kDa
Atom Count: 2,707
Modelled Residue Count: 309
Deposited Residue Count: 309
Unique protein chains: 2

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Factor VII light chain	A [auth H]	254	Homo sapiens	Mutation(s): 0 Gene Names: F7 EC: 3.4.21.21
UniProt & NIH Common Fund Data Resources
Find proteins for P08709 (Homo sapiens) Explore P08709 Go to UniProtKB: P08709
PHAROS: P08709 GTEx: ENSG00000057593
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P08709
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Factor VII heavy chain	B [auth L]	55	Homo sapiens	Mutation(s): 0 Gene Names: F7 EC: 3.4.21.21
UniProt & NIH Common Fund Data Resources
Find proteins for P08709 (Homo sapiens) Explore P08709 Go to UniProtKB: P08709
PHAROS: P08709 GTEx: ENSG00000057593
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P08709
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
1OJ Query on 1OJ Download Ideal Coordinates CCD File SDF format, chain C [auth H] MOL2 format, chain C [auth H]	C [auth H]	(2R)-2-[3-ethoxy-4-(propan-2-yloxy)phenyl]-2-(isoquinolin-6-ylamino)-N-[(3-sulfamoylphenyl)sulfonyl]ethanamide C₂₈ H₃₀ N₄ O₇ S₂ QHVDUHFNSHQJRC-HHHXNRCGSA-N		Interactions Focus chain C [auth H] Interactions & Density Focus chain C [auth H]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain E [auth H] SDF format, chain F [auth H] SDF format, chain G [auth H] SDF format, chain H MOL2 format, chain E [auth H] MOL2 format, chain F [auth H] MOL2 format, chain G [auth H] MOL2 format, chain H	E [auth H], F [auth H], G [auth H], H	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain E [auth H] Focus chain F [auth H] Focus chain G [auth H] Focus chain H Interactions & Density Focus chain E [auth H] Focus chain F [auth H] Focus chain G [auth H] Focus chain H
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain I [auth H] SDF format, chain J [auth H] SDF format, chain K [auth H] SDF format, chain L [auth H] MOL2 format, chain I [auth H] MOL2 format, chain J [auth H] MOL2 format, chain K [auth H] MOL2 format, chain L [auth H]	I [auth H], J [auth H], K [auth H], L [auth H]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain I [auth H] Focus chain J [auth H] Focus chain K [auth H] Focus chain L [auth H] Interactions & Density Focus chain I [auth H] Focus chain J [auth H] Focus chain K [auth H] Focus chain L [auth H]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain D [auth H] MOL2 format, chain D [auth H]	D [auth H]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain D [auth H] Interactions & Density Focus chain D [auth H]

Binding Affinity Annotations
ID	Source	Binding Affinity
1OJ	PDBBind: 4JYV	Ki: 17 (nM) from 1 assay(s)
	Binding MOAD: 4JYV	Ki: 17 (nM) from 1 assay(s)
	BindingDB: 4JYV	Ki: min: 17, max: 32 (nM) from 2 assay(s)