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- PDB-5czm: Crystal structure of a mutated catalytic domain of Human MMP12 in... -

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Basic information

Entry
Database: PDB / ID: 5czm
TitleCrystal structure of a mutated catalytic domain of Human MMP12 in complex with RXP470
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE / Matrix / Metallo Elastase / MMP12 / human / RXP470 / Macrophage
Function / homology
Function and homology information


macrophage elastase / negative regulation of endothelial cell-matrix adhesion / bronchiole development / positive regulation of epithelial cell proliferation involved in wound healing / elastin catabolic process / regulation of defense response to virus by host / positive regulation of type I interferon-mediated signaling pathway / wound healing, spreading of epidermal cells / negative regulation of type I interferon-mediated signaling pathway / lung alveolus development ...macrophage elastase / negative regulation of endothelial cell-matrix adhesion / bronchiole development / positive regulation of epithelial cell proliferation involved in wound healing / elastin catabolic process / regulation of defense response to virus by host / positive regulation of type I interferon-mediated signaling pathway / wound healing, spreading of epidermal cells / negative regulation of type I interferon-mediated signaling pathway / lung alveolus development / response to amyloid-beta / Collagen degradation / collagen catabolic process / positive regulation of interferon-alpha production / extracellular matrix disassembly / core promoter sequence-specific DNA binding / collagen binding / Degradation of the extracellular matrix / extracellular matrix organization / extracellular matrix / metalloendopeptidase activity / cellular response to virus / protein import into nucleus / endopeptidase activity / sequence-specific DNA binding / serine-type endopeptidase activity / calcium ion binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / proteolysis / extracellular space / extracellular region / zinc ion binding / nucleus / cytoplasm
Similarity search - Function
Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidoglycan binding-like / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / Hemopexin-like repeats / Hemopexin-like domain superfamily / Hemopexin / Putative peptidoglycan binding domain ...Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidoglycan binding-like / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / Hemopexin-like repeats / Hemopexin-like domain superfamily / Hemopexin / Putative peptidoglycan binding domain / Hemopexin repeat profile. / Hemopexin-like repeats. / Peptidase M10A / Peptidase M10A, catalytic domain / Peptidase M10, metallopeptidase / Matrixin / PGBD-like superfamily / Peptidase, metallopeptidase / Zinc-dependent metalloprotease / Collagenase (Catalytic Domain) / Collagenase (Catalytic Domain) / Metallopeptidase, catalytic domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
N-[(2S)-3-[(S)-(4-BROMOPHENYL)(HYDROXY)PHOSPHORYL]-2-{[3-(3'-CHLOROBIPHENYL-4-YL)-1,2-OXAZOL-5-YL]METHYL}PROPANOYL]-L-ALPHA-GLUTAMYL-L-ALPHA-GLUTAMINE / Chem-R47 / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.303 Å
AuthorsRouanet-Mehouas, C. / Roselia, L. / Devel, L. / Dive, V. / Stura, E.A.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Zinc-Metalloproteinase Inhibitors: Evaluation of the Complex Role Played by the Zinc-Binding Group on Potency and Selectivity.
Authors: Rouanet-Mehouas, C. / Czarny, B. / Beau, F. / Cassar-Lajeunesse, E. / Stura, E.A. / Dive, V. / Devel, L.
History
DepositionJul 31, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 10, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2016Group: Database references / Non-polymer description
Revision 1.2Jan 11, 2017Group: Database references
Revision 1.3Jan 25, 2017Group: Database references
Revision 1.4Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,6277
Polymers17,5581
Non-polymers1,0696
Water4,828268
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-23 kcal/mol
Surface area8020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.970, 63.290, 35.910
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-419-

HOH

21A-483-

HOH

31A-663-

HOH

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Components

#1: Protein Macrophage metalloelastase / MME / Macrophage elastase / hME / Matrix metalloproteinase-12 / MMP-12


Mass: 17557.568 Da / Num. of mol.: 1 / Fragment: UNP residues 106-263 / Mutation: F171D K241A
Source method: isolated from a genetically manipulated source
Details: MMP12 F171D K241A mutant for calorimetric studies Catalytic domain (UNP residues 106-263)
Source: (gene. exp.) Homo sapiens (human) / Gene: MMP12, HME / Plasmid: PET24A / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P39900, macrophage elastase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-R47 / N-[(2S)-3-[(S)-(4-bromophenyl)(hydroxy)phosphoryl]-2-{[3-(3'-chlorobiphenyl-4-yl)-1,2-oxazol-5-yl]methyl}propanoyl]-L-alpha-glutamyl-L-alpha-glutamine / RXP470.1


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 818.004 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C35H35BrClN4O10P
References: N-[(2S)-3-[(S)-(4-BROMOPHENYL)(HYDROXY)PHOSPHORYL]-2-{[3-(3'-CHLOROBIPHENYL-4-YL)-1,2-OXAZOL-5-YL]METHYL}PROPANOYL]-L-ALPHA-GLUTAMYL-L-ALPHA-GLUTAMINE
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 268 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.23 Å3/Da / Density % sol: 44.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9.5
Details: Protein : MMP12h F67D K241A 850 micro-M + 10mM AHA Drop : 1 micro-L protein + 0.35 micro-l inhibitor(1.5 milli-M, DMSO) Precipitant : 20% PEG4K, 0.2 M TRIS pH9.5 Cryo protectant : 5% ...Details: Protein : MMP12h F67D K241A 850 micro-M + 10mM AHA Drop : 1 micro-L protein + 0.35 micro-l inhibitor(1.5 milli-M, DMSO) Precipitant : 20% PEG4K, 0.2 M TRIS pH9.5 Cryo protectant : 5% diethylene glycol, 0% ethylene glycol, 5% MPD + 5% glycerol, 5% 2,3-butanediol, 5mM NDSB 201, 25% PEG 6K, 100mM TRIS HCl, pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: N2 stream
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9184 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 12, 2015
Details: convex horizontal pre-focussing mirror (HPM) and a pair of focusing bimorph mirrors in Kirkpatrick-Baez (KB)
RadiationMonochromator: cryogenically cooled channel-cut Si[111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.3→46.632 Å / Num. all: 74325 / Num. obs: 74004 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 6.5 % / Rmerge(I) obs: 0.207 / Rsym value: 0.191 / Net I/σ(I): 9.96
Reflection shellResolution: 1.3→1.38 Å / Redundancy: 6.14 % / Rmerge(I) obs: 2.097 / Mean I/σ(I) obs: 1.1 / % possible all: 97.5

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Processing

Software
NameVersionClassification
PHENIX1.8_1069refinement
MxCuBEdata collection
XDSdata reduction
MOLREPphasing
Cootmodel building
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GQL

4gql


Resolution: 1.303→28.451 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 16.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1739 1954 5 %RANDOM
Rwork0.1454 ---
obs0.1468 39081 99.72 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.303→28.451 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1242 0 57 268 1567
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061442
X-RAY DIFFRACTIONf_angle_d1.0571977
X-RAY DIFFRACTIONf_dihedral_angle_d14.101514
X-RAY DIFFRACTIONf_chiral_restr0.07196
X-RAY DIFFRACTIONf_plane_restr0.005265
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3031-1.33570.37631340.32552535X-RAY DIFFRACTION97
1.3357-1.37180.2491380.23572635X-RAY DIFFRACTION100
1.3718-1.41220.24991370.21122601X-RAY DIFFRACTION100
1.4122-1.45780.22621380.18732624X-RAY DIFFRACTION100
1.4578-1.50990.20881380.17652620X-RAY DIFFRACTION100
1.5099-1.57030.17561390.15272629X-RAY DIFFRACTION100
1.5703-1.64180.16391390.12662647X-RAY DIFFRACTION100
1.6418-1.72840.15761390.12542642X-RAY DIFFRACTION100
1.7284-1.83660.16811380.11962616X-RAY DIFFRACTION100
1.8366-1.97840.1391400.11612666X-RAY DIFFRACTION100
1.9784-2.17740.14941400.12092667X-RAY DIFFRACTION100
2.1774-2.49240.16841410.1342677X-RAY DIFFRACTION100
2.4924-3.13950.20281430.13842719X-RAY DIFFRACTION100
3.1395-28.45830.14641500.14722849X-RAY DIFFRACTION100

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