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- PDB-6enm: Crystal structure of MMP12 in complex with hydroxamate inhibitor ... -

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Basic information

Entry
Database: PDB / ID: 6enm
TitleCrystal structure of MMP12 in complex with hydroxamate inhibitor LP168.
ComponentsMacrophage metalloelastase
KeywordsHYDROLASE / metzincin / carboxylate inhibitor alternative zinc-binding groups
Function / homology
Function and homology information


macrophage elastase / negative regulation of endothelial cell-matrix adhesion via fibronectin / 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 via fibronectin / 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 / positive regulation of interferon-alpha production / collagen catabolic process / 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
Chem-LPW / Macrophage metalloelastase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.59 Å
AuthorsVera, L. / Nuti, E. / Rossello, A. / Stura, E.A.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Development of Thioaryl-Based Matrix Metalloproteinase-12 Inhibitors with Alternative Zinc-Binding Groups: Synthesis, Potentiometric, NMR, and Crystallographic Studies.
Authors: Nuti, E. / Cuffaro, D. / Bernardini, E. / Camodeca, C. / Panelli, L. / Chaves, S. / Ciccone, L. / Tepshi, L. / Vera, L. / Orlandini, E. / Nencetti, S. / Stura, E.A. / Santos, M.A. / Dive, V. / Rossello, A.
History
DepositionOct 5, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 16, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 6, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 17, 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 / 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.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Macrophage metalloelastase
B: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,52814
Polymers35,2312
Non-polymers1,29712
Water7,134396
1
A: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2647
Polymers17,6161
Non-polymers6486
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Macrophage metalloelastase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,2647
Polymers17,6161
Non-polymers6486
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.410, 67.090, 68.440
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 17615.670 Da / Num. of mol.: 2 / Mutation: F171D
Source method: isolated from a genetically manipulated source
Details: matrix metalloprotein 12 / Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Gene: MMP12, HME / Production host: Escherichia coli (E. coli) / References: UniProt: P39900, macrophage elastase
#2: Chemical ChemComp-LPW / 2-[2-[4-(4-methoxyphenyl)phenyl]sulfonylphenyl]-~{N}-oxidanyl-ethanamide


Mass: 397.444 Da / Num. of mol.: 2 / Mutation: F171D
Source method: isolated from a genetically manipulated source
Formula: C21H19NO5S / Details: matrix metalloprotein 12 / Source: (gene. exp.) Homo sapiens (human) / Cell: macrophage / Production host: Escherichia coli (E. coli) / References: macrophage elastase
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 396 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2 Å3/Da / Density % sol: 38.53 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Drops: 1 micro-L hMMP12 at 927 micro-M + 10 mM acetohydroxamic acid, LP168 at 1 milli-M and 1 micro-L precipitant. Precipitant: 17% PEG 20K, 0.2 M imidazole malate, pH 8.5, 0.250 M NaCl ...Details: Drops: 1 micro-L hMMP12 at 927 micro-M + 10 mM acetohydroxamic acid, LP168 at 1 milli-M and 1 micro-L precipitant. Precipitant: 17% PEG 20K, 0.2 M imidazole malate, pH 8.5, 0.250 M NaCl cryoprotectant: 27% PEG8K, 15% MPEG550, 10% glycerol, 90mM Tris-HCl, pH 8.0
PH range: 8.0-8.5 / Temp details: cooled incubator

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryostream
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.9184 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 20, 2010 / Details: mirrors
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.59→47.91 Å / Num. obs: 38794 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 7.93 % / Rsym value: 0.123 / Net I/σ(I): 12.1
Reflection shellResolution: 1.59→1.68 Å / Redundancy: 8.11 % / Mean I/σ(I) obs: 2.9 / Rsym value: 0.85 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4H76

4h76


Resolution: 1.59→47.91 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.96 / SU B: 1.884 / SU ML: 0.065 / Cross valid method: THROUGHOUT / ESU R: 0.098 / ESU R Free: 0.093 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.202 1934 5 %RANDOM
Rwork0.174 ---
obs0.175 36745 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 18.65 Å2
Baniso -1Baniso -2Baniso -3
1--1.15 Å20 Å20 Å2
2--1.77 Å20 Å2
3----0.63 Å2
Refinement stepCycle: LAST / Resolution: 1.59→47.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2372 0 66 396 2834
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0192698
X-RAY DIFFRACTIONr_bond_other_d0.0060.022319
X-RAY DIFFRACTIONr_angle_refined_deg1.7671.9413688
X-RAY DIFFRACTIONr_angle_other_deg1.09335369
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6955341
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.7723.206131
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.55615394
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5541515
X-RAY DIFFRACTIONr_chiral_restr0.1330.2370
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.023190
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02643
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.0211.5741316
X-RAY DIFFRACTIONr_mcbond_other1.9891.571315
X-RAY DIFFRACTIONr_mcangle_it2.8742.3551673
X-RAY DIFFRACTIONr_mcangle_other2.8782.3561674
X-RAY DIFFRACTIONr_scbond_it3.0611.8961382
X-RAY DIFFRACTIONr_scbond_other3.0611.8951382
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.5812.7222015
X-RAY DIFFRACTIONr_long_range_B_refined6.46921.2883480
X-RAY DIFFRACTIONr_long_range_B_other6.1120.183345
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.59→1.63 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.286 142 -
Rwork0.266 2684 -
obs--100 %

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