2I47

Crystal structure of catalytic domain of TACE with inhibitor

PDB DOI: https://doi.org/10.2210/pdb2I47/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Mutation(s): Yes

Deposited: 2006-08-21 Released: 2006-12-05
Deposition Author(s): Xu, W., Condon, J.S., Lovering, F.E.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.90 Å
R-Value Free: 0.227
R-Value Work: 0.198
R-Value Observed: 0.198

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Identification of potent and selective TACE inhibitors via the S1 pocket.

Condon, J.S., Joseph-McCarthy, D., Levin, J.I., Lombart, H.G., Lovering, F.E., Sun, L., Wang, W., Xu, W., Zhang, Y.

(2007) Bioorg Med Chem Lett 17: 34-39

PubMed: 17064892 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2006.10.004
Primary Citation of Related Structures:
2I47

PubMed Abstract:
By focusing on the P1 portion of the piperidine beta-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14.

Organizational Affiliation

Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.

Macromolecule Content

Total Structure Weight: 132.5 kDa
Atom Count: 8,926
Modelled Residue Count: 1,018
Deposited Residue Count: 1,152
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
ADAM 17	A, B, C, D	288	Homo sapiens	Mutation(s): 2 EC: 3.4.24.86
UniProt & NIH Common Fund Data Resources
Find proteins for P78536 (Homo sapiens) Explore P78536 Go to UniProtKB: P78536
PHAROS: P78536 GTEx: ENSG00000151694
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P78536
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
KGY Query on KGY Download Ideal Coordinates CCD File SDF format, chain J [auth C] SDF format, chain L [auth D] MOL2 format, chain J [auth C] MOL2 format, chain L [auth D]	J [auth C], L [auth D]	4-({[4-(BUT-2-YN-1-YLOXY)PHENYL]SULFONYL}METHYL)-1-[(3,5-DIMETHYLISOXAZOL-4-YL)SULFONYL]-N-HYDROXYPIPERIDINE-4-CARBOXAMIDE C₂₂ H₂₇ N₃ O₈ S₂ BIGQJQKSDHOEOM-UHFFFAOYSA-N		Interactions Focus chain J [auth C] Focus chain L [auth D] Interactions & Density Focus chain J [auth C] Focus chain L [auth D]
INN Query on INN Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain H [auth B] MOL2 format, chain F [auth A] MOL2 format, chain H [auth B]	F [auth A], H [auth B]	N-{(2R)-2-[2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoyl}-3-methyl-L-valyl-N-(2-aminoethyl)-L-alaninamide C₁₉ H₃₇ N₅ O₅ LMIQCBIEAHJAMZ-GZBFAFLISA-N		Interactions Focus chain F [auth A] Focus chain H [auth B] Interactions & Density Focus chain F [auth A] Focus chain H [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain G [auth B] SDF format, chain I [auth C] SDF format, chain K [auth D] MOL2 format, chain E [auth A] MOL2 format, chain G [auth B] MOL2 format, chain I [auth C] MOL2 format, chain K [auth D]	E [auth A], G [auth B], I [auth C], K [auth D]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D] Interactions & Density Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D]

Binding Affinity Annotations
ID	Source	Binding Affinity
KGY	Binding MOAD: 2I47	IC50: 2.2 (nM) from 1 assay(s)
	BindingDB: 2I47	IC50: 2.2 (nM) from 1 assay(s)
	PDBBind: 2I47	IC50: 2.2 (nM) from 1 assay(s)

Biologically Interesting Molecules (External Reference) 1 Unique

Entity ID: 3
ID	Chains	Name	Type/Class	2D Diagram	3D Interactions
PRD_000919 (INN) Query on PRD_000919	F [auth A], H [auth B]	3,N(D,L-[2-(HYDROXYAMINO-CARBONYL)METHYL]-4-METHYL PENTANOYL)L-3-(TERT-BUTYL)GLYCYL-L-ALANINE	Peptide-like / Enzyme inhibitor		Interactions Focus chain F [auth A] Focus chain H [auth B] Interactions & Density Focus chain F [auth A] Focus chain H [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.90 Å
R-Value Free: 0.227
R-Value Work: 0.198
R-Value Observed: 0.198
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 61.775	α = 90
b = 126.193	β = 107.41
c = 81.224	γ = 90

Software Package:

Software Name	Purpose
HKL-2000	data collection
AMoRE	phasing
CNS	refinement
DENZO	data reduction
SCALEPACK	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2006-12-05

Deposition Author(s):

Xu, W.

Condon, J.S.

Lovering, F.E.

Revision History (Full details and data files)

Version 1.0: 2006-12-05
Type: Initial release
Version 1.1: 2008-05-01
Changes: Version format compliance
Version 1.2: 2011-07-13
Changes: Non-polymer description, Version format compliance
Version 1.3: 2013-02-27
Changes: Other
Version 1.4: 2021-10-20
Changes: Database references, Derived calculations

Prepare Data

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Deposit Data

Help and Resources

2I47

Crystal structure of catalytic domain of TACE with inhibitor

Identification of potent and selective TACE inhibitors via the S1 pocket.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

Expand

Entity ID: 3

Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)