3Q2H

Adamts1 in complex with N-hydroxyformamide inhibitors of ADAM-TS4

PDB DOI: https://doi.org/10.2210/pdb3Q2H/pdb

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

Deposited: 2010-12-20 Released: 2011-03-30
Deposition Author(s): Gerhardt, S., Hargreaves, D.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.33 Å
R-Value Free: 0.297
R-Value Work: 0.236
R-Value Observed: 0.239

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis

De Savi, C., Pape, A., Cumming, J.G., Ting, A., Smith, P.D., Burrows, J.N., Mills, M., Davies, C., Lamont, S., Milne, D., Cook, C., Moore, P., Sawyer, Y., Gerhardt, S.

(2011) Bioorg Med Chem Lett 21: 1376-1381

PubMed: 21300546 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2011.01.036
Primary Citation of Related Structures:
3Q2G, 3Q2H

PubMed Abstract:
Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.

Organizational Affiliation

Respiratory and Inflammation Research Area, AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK. chris.desavi2@astrazeneca.com

Macromolecule Content

Total Structure Weight: 67.75 kDa
Atom Count: 4,545
Modelled Residue Count: 566
Deposited Residue Count: 594
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
A disintegrin and metalloproteinase with thrombospondin motifs 1	A, B	297	Homo sapiens	Mutation(s): 0 Gene Names: ADAMTS1 EC: 3.4.24
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UHI8 (Homo sapiens) Explore Q9UHI8 Go to UniProtKB: Q9UHI8
PHAROS: Q9UHI8 GTEx: ENSG00000154734
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9UHI8
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
QHF Query on QHF Download Ideal Coordinates CCD File SDF format, chain EA [auth B] SDF format, chain T [auth A] MOL2 format, chain EA [auth B] MOL2 format, chain T [auth A]	EA [auth B], T [auth A]	N-[(2S,4S)-1-({4-[2-(3,5-dimethyl-1,2-oxazol-4-yl)ethyl]piperidin-1-yl}sulfonyl)-4-(5-fluoropyrimidin-2-yl)-2-methylpentan-2-yl]-N-hydroxyformamide C₂₃ H₃₄ F N₅ O₅ S UAGAABCJKYADIR-HJPURHCSSA-N		Interactions Focus chain EA [auth B] Focus chain T [auth A] Interactions & Density Focus chain EA [auth B] Focus chain T [auth A]
CD Query on CD Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain I [auth A] SDF format, chain W [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain I [auth A] MOL2 format, chain W [auth B]	D [auth A], E [auth A], I [auth A], W [auth B]	CADMIUM ION Cd WLZRMCYVCSSEQC-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain I [auth A] Focus chain W [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain I [auth A] Focus chain W [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain U [auth B] MOL2 format, chain C [auth A] MOL2 format, chain U [auth B]	C [auth A], U [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain U [auth B] Interactions & Density Focus chain C [auth A] Focus chain U [auth B]
NI Query on NI Download Ideal Coordinates CCD File SDF format, chain AA [auth B] SDF format, chain BA [auth B] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain M [auth A] SDF format, chain N [auth A] SDF format, chain O [auth A] SDF format, chain P [auth A] SDF format, chain V [auth B] SDF format, chain X [auth B] SDF format, chain Z [auth B] MOL2 format, chain AA [auth B] MOL2 format, chain BA [auth B] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain M [auth A] MOL2 format, chain N [auth A] MOL2 format, chain O [auth A] MOL2 format, chain P [auth A] MOL2 format, chain V [auth B] MOL2 format, chain X [auth B] MOL2 format, chain Z [auth B]	AA [auth B] BA [auth B] F [auth A] G [auth A] H [auth A] AA [auth B], BA [auth B], F [auth A], G [auth A], H [auth A], J [auth A], K [auth A], M [auth A], N [auth A], O [auth A], P [auth A], V [auth B], X [auth B], Z [auth B]	NICKEL (II) ION Ni VEQPNABPJHWNSG-UHFFFAOYSA-N		Interactions Focus chain AA [auth B] Focus chain BA [auth B] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A] Focus chain P [auth A] Focus chain V [auth B] Focus chain X [auth B] Focus chain Z [auth B] Interactions & Density Focus chain AA [auth B] Focus chain BA [auth B] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain O [auth A] Focus chain P [auth A] Focus chain V [auth B] Focus chain X [auth B] Focus chain Z [auth B]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain L [auth A] SDF format, chain Q [auth A] SDF format, chain Y [auth B] MOL2 format, chain L [auth A] MOL2 format, chain Q [auth A] MOL2 format, chain Y [auth B]	L [auth A], Q [auth A], Y [auth B]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain L [auth A] Focus chain Q [auth A] Focus chain Y [auth B] Interactions & Density Focus chain L [auth A] Focus chain Q [auth A] Focus chain Y [auth B]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain CA [auth B] SDF format, chain DA [auth B] SDF format, chain R [auth A] SDF format, chain S [auth A] MOL2 format, chain CA [auth B] MOL2 format, chain DA [auth B] MOL2 format, chain R [auth A] MOL2 format, chain S [auth A]	CA [auth B], DA [auth B], R [auth A], S [auth A]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain CA [auth B] Focus chain DA [auth B] Focus chain R [auth A] Focus chain S [auth A] Interactions & Density Focus chain CA [auth B] Focus chain DA [auth B] Focus chain R [auth A] Focus chain S [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
QHF	PDBBind: 3Q2H	IC50: 0.69 (nM) from 1 assay(s)
QHF	Binding MOAD: 3Q2H	IC50: 0.69 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.33 Å
R-Value Free: 0.297
R-Value Work: 0.236
R-Value Observed: 0.239
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 50.859	α = 90
b = 63.328	β = 91.24
c = 110.844	γ = 90

Software Package:

Software Name	Purpose
StructureStudio	data collection
AMoRE	phasing
REFMAC	refinement
d*TREK	data reduction
d*TREK	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2011-03-30

Deposition Author(s):

Gerhardt, S.

Hargreaves, D.

Revision History (Full details and data files)

Version 1.0: 2011-03-30
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2023-11-01
Changes: Data collection, Database references, Derived calculations, Refinement description