5CUH | pdb_00005cuh

Crystal structure MMP-9 complexes with a constrained hydroxamate based inhibitor LT4

PDB DOI: https://doi.org/10.2210/pdb5CUH/pdb

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

Deposited: 2015-07-24 Released: 2016-02-10
Deposition Author(s): Tepshi, L., Vera, L., Nuti, E., Rosalia, L., Rossello, A., Stura, E.A.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.83 Å
R-Value Free:
0.214 (Depositor), 0.210 (DCC)
R-Value Work:
0.173 (Depositor), 0.170 (DCC)
R-Value Observed:
0.175 (Depositor)

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

Discovery of a new selective inhibitor of A Disintegrin And Metalloprotease 10 (ADAM-10) able to reduce the shedding of NKG2D ligands in Hodgkin's lymphoma cell models.

Camodeca, C., Nuti, E., Tepshi, L., Boero, S., Tuccinardi, T., Stura, E.A., Poggi, A., Zocchi, M.R., Rossello, A.

(2016) Eur J Med Chem 111: 193-201

PubMed: 26871660 Search on PubMed
DOI: https://doi.org/10.1016/j.ejmech.2016.01.053
Primary Citation of Related Structures:
5CUH

PubMed Abstract:
Hodgkin's lymphoma (HL) is the most common malignant lymphoma in young adults in the western world. This disease is characterized by an overexpression of ADAM-10 with increased release of NKG2D ligands, involved in an impaired immune response against tumor cells. We designed and synthesized two new ADAM-10 selective inhibitors, 2 and 3 based on previously published ADAM-17 selective inhibitor 1. The most promising compound was the thiazolidine derivative 3, with nanomolar activity for ADAM-10, high selectivity over ADAM-17 and MMPs and good efficacy in reducing the shedding of NKG2D ligands (MIC-B and ULBP3) in three different HL cell lines at non-toxic doses. Molecular modeling studies were used to drive the design and X-ray crystallography studies were carried out to explain the selectivity of 3 for ADAM-10 over MMPs.

Organizational Affiliation

Division of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy.

Macromolecule Content

Total Structure Weight: 38.48 kDa
Atom Count: 3,203
Modelled Residue Count: 328
Deposited Residue Count: 328
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Matrix metalloproteinase-9,Matrix metalloproteinase-9	A, B	164	Homo sapiens	Mutation(s): 0 Gene Names: MMP9, CLG4B EC: 3.4.24.35
UniProt & NIH Common Fund Data Resources
Find proteins for P14780 (Homo sapiens) Explore P14780 Go to UniProtKB: P14780
PHAROS: P14780 GTEx: ENSG00000100985
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P14780
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
LTQ Query on LTQ Download Ideal Coordinates CCD File SDF format, chain Q [auth B] SDF format, chain H [auth A] MOL2 format, chain Q [auth B] MOL2 format, chain H [auth A] mmCIF format, chain Q [auth B] mmCIF format, chain H [auth A]	H [auth A], Q [auth B]	(4S)-3-{[4-(4-cyano-2-methylphenyl)piperazin-1-yl]sulfonyl}-N-hydroxy-1,3-thiazolidine-4-carboxamide C₁₆ H₂₁ N₅ O₄ S₂ UGVOWFLXYXPRQV-OAHLLOKOSA-N		Interactions Focus chain H [auth A] Focus chain Q [auth B] Interactions & Density Focus chain H [auth A] Focus chain Q [auth B]
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 K [auth A] SDF format, chain U [auth B] MOL2 format, chain K [auth A] MOL2 format, chain U [auth B] mmCIF format, chain K [auth A] mmCIF format, chain U [auth B]	K [auth A], U [auth B]	S-1,2-PROPANEDIOL C₃ H₈ O₂ DNIAPMSPPWPWGF-VKHMYHEASA-N		Interactions Focus chain K [auth A] Focus chain U [auth B] Interactions & Density Focus chain K [auth A] Focus chain U [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain L [auth B] SDF format, chain M [auth B] SDF format, chain C [auth A] MOL2 format, chain D [auth A] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] MOL2 format, chain C [auth A] mmCIF format, chain D [auth A] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B] mmCIF format, chain C [auth A]	C [auth A], D [auth A], L [auth B], M [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain D [auth A] Focus chain L [auth B] Focus chain M [auth B] Interactions & Density Focus chain C [auth A] Focus chain D [auth A] Focus chain L [auth B] Focus chain M [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain R [auth B] SDF format, chain S [auth B] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B]	I [auth A], J [auth A], R [auth B], S [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Focus chain J [auth A] Focus chain R [auth B] Focus chain S [auth B] Interactions & Density Focus chain I [auth A] 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 E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain N [auth B] SDF format, chain O [auth B] SDF format, chain P [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain N [auth B] MOL2 format, chain O [auth B] MOL2 format, chain P [auth B] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain N [auth B] mmCIF format, chain O [auth B] mmCIF format, chain P [auth B]	E [auth A] F [auth A] G [auth A] N [auth B] O [auth B] E [auth A], F [auth A], G [auth A], N [auth B], O [auth B], P [auth B]	CALCIUM ION Ca BHPQYMZQTOCNFJ-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
LTQ	BindingDB: 5CUH	IC50: 2.40e+4 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.83 Å
R-Value Free: 0.214 (Depositor), 0.210 (DCC)
R-Value Work: 0.173 (Depositor), 0.170 (DCC)
R-Value Observed: 0.175 (Depositor)

Space Group: P 2₁ 2₁ 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 74.68	α = 90
b = 97.79	β = 90
c = 43.49	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: 2016-02-10

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2016-02-10
Type: Initial release
Version 1.1: 2016-04-20
Changes: Database references
Version 1.2: 2017-09-27
Changes: Data collection, Database references, Derived calculations
Version 1.3: 2023-11-08
Changes: Data collection, Database references, Derived calculations, Refinement description

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Help and Resources

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Crystal structure MMP-9 complexes with a constrained hydroxamate based inhibitor LT4

Discovery of a new selective inhibitor of A Disintegrin And Metalloprotease 10 (ADAM-10) able to reduce the shedding of NKG2D ligands in Hodgkin's lymphoma cell models.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

Expand