5I0L

Crystal structure of the catalytic domain of MMP-12 in complex with a selective sugar-conjugated arylsulfonamide carboxylate water-soluble inhibitor (DC27).

PDB DOI: https://doi.org/10.2210/pdb5I0L/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2016-02-04 Released: 2016-07-06
Deposition Author(s): Stura, E.A., Rosalia, L., Cuffaro, D., Tepshi, L., Ciccone, L., Rossello, A.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.45 ?
R-Value Free: 0.253
R-Value Work: 0.175
R-Value Observed: 0.179

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors.

Nuti, E., Cuffaro, D., D'Andrea, F., Rosalia, L., Tepshi, L., Fabbi, M., Carbotti, G., Ferrini, S., Santamaria, S., Camodeca, C., Ciccone, L., Orlandini, E., Nencetti, S., Stura, E.A., Dive, V., Rossello, A.

(2016) ChemMedChem 11: 1626-1637

PubMed: 27356908 Search on PubMed
DOI: https://doi.org/10.1002/cmdc.201600235
Primary Citation of Related Structures:
5I0L, 5I12, 5I2Z, 5I3M, 5I43, 5I4O

PubMed Abstract:
Matrix metalloproteinase-12 (MMP-12) can be considered an attractive target to study selective inhibitors useful in the development of new therapies for lung and cardiovascular diseases. In this study, a new series of arylsulfonamide carboxylates, with increased hydrophilicity resulting from conjugation with a β-N-acetyl-d-glucosamine moiety, were designed and synthesized as MMP-12 selective inhibitors. Their inhibitory activity was evaluated on human MMPs by using the fluorimetric assay, and a crystallographic analysis was performed to characterize their binding mode. Among these glycoconjugates, a nanomolar MMP-12 inhibitor with improved water solubility, compound 3 [(R)-2-(N-(2-(3-(2-acetamido-2-deoxy-β-d-glucopyranosyl)thioureido)ethyl)biphenyl-4-ylsulfonamido)-3-methylbutanoic acid], was identified.

Organizational Affiliation

Department of Pharmacy, University of Pisa, via Bonanno?6, 56126, Pisa, Italy.

Macromolecule Content

Total Structure Weight: 37.71 kDa
Atom Count: 3,000
Modelled Residue Count: 317
Deposited Residue Count: 318
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Macrophage metalloelastase	A, B	159	Homo sapiens	Mutation(s): 1 Gene Names: MMP12, HME EC: 3.4.24.65
UniProt & NIH Common Fund Data Resources
Find proteins for P39900 (Homo sapiens) Explore P39900 Go to UniProtKB: P39900
PHAROS: P39900 GTEx: ENSG00000262406
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P39900
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 7 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
H27 Query on H27 Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain L [auth B] MOL2 format, chain C [auth A] MOL2 format, chain L [auth B] mmCIF format, chain C [auth A] mmCIF format, chain L [auth B]	C [auth A], L [auth B]	(2R)-2-[{(E)-2-[({(2R,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}carbamothioyl)amino]ethenyl}(biphenyl-4-ylsulfonyl)amino]-3-methylbutanoic acid C₃₄ H₄₂ N₄ O₁₂ S₂ NIEQAOCPXJWQAU-NPCCVVQBSA-N		Interactions Focus chain C [auth A] Focus chain L [auth B] Interactions & Density Focus chain C [auth A] Focus chain L [auth B]
PEG Query on PEG Download Ideal Coordinates CCD File SDF format, chain K [auth A] MOL2 format, chain K [auth A] mmCIF format, chain K [auth A]	K [auth A]	DI(HYDROXYETHYL)ETHER C₄ H₁₀ O₃ MTHSVFCYNBDYFN-UHFFFAOYSA-N		Interactions Focus chain K [auth A] Interactions & Density Focus chain K [auth A]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain T [auth B] MOL2 format, chain T [auth B] mmCIF format, chain T [auth B]	T [auth B]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain T [auth B] Interactions & Density Focus chain T [auth B]
PGO Query on PGO Download Ideal Coordinates CCD File SDF format, chain I [auth A] MOL2 format, chain I [auth A] mmCIF format, chain I [auth A]	I [auth A]	S-1,2-PROPANEDIOL C₃ H₈ O₂ DNIAPMSPPWPWGF-VKHMYHEASA-N		Interactions Focus chain I [auth A] Interactions & Density Focus chain I [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain M [auth B] SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain N [auth B] MOL2 format, chain M [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain N [auth B] mmCIF format, chain M [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain N [auth B]	D [auth A], E [auth A], M [auth B], N [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain M [auth B] Focus chain N [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain M [auth B] Focus chain N [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain J [auth A] SDF format, chain R [auth B] SDF format, chain S [auth B] MOL2 format, chain J [auth A] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] mmCIF format, chain J [auth A] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B]	J [auth A], R [auth B], S [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain J [auth A] Focus chain R [auth B] Focus chain S [auth B] Interactions & Density Focus chain J [auth A] Focus chain R [auth B] Focus chain S [auth B]
CA Query on CA Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain P [auth B] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain O [auth B] SDF format, chain Q [auth B] MOL2 format, chain H [auth A] MOL2 format, chain P [auth B] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain O [auth B] MOL2 format, chain Q [auth B] mmCIF format, chain H [auth A] mmCIF format, chain P [auth B] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain O [auth B] mmCIF format, chain Q [auth B]	F [auth A] G [auth A] H [auth A] O [auth B] P [auth B] F [auth A], G [auth A], H [auth A], O [auth B], P [auth B], Q [auth B]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.45 ?
R-Value Free: 0.253
R-Value Work: 0.175
R-Value Observed: 0.179
Space Group: P 1 2₁ 1

Unit Cell:

Length ( ? )	Angle ( ? )
a = 39.09	α = 90
b = 62.86	β = 102.54
c = 63.75	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
XDS	data reduction
XSCALE	data scaling
REFMAC	phasing
Coot	model building

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2016-07-06

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2016-07-06
Type: Initial release
Version 1.1: 2016-07-13
Changes: Database references
Version 1.2: 2016-08-17
Changes: Database references
Version 1.3: 2024-01-10
Changes: Data collection, Database references, Derived calculations, Refinement description

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Help and Resources

5I0L

Crystal structure of the catalytic domain of MMP-12 in complex with a selective sugar-conjugated arylsulfonamide carboxylate water-soluble inhibitor (DC27).

Sugar-Based Arylsulfonamide Carboxylates as Selective and Water-Soluble Matrix Metalloproteinase-12 Inhibitors.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

Expand

Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)