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- PDB-3kek: Crystal Structure of Human MMP-13 complexed with a (pyridin-4-yl)... -

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Basic information

Entry
Database: PDB / ID: 3kek
TitleCrystal Structure of Human MMP-13 complexed with a (pyridin-4-yl)-2H-tetrazole compound
ComponentsCollagenase 3
KeywordsHYDROLASE/HYDROLASE INHIBITOR / S1' inhibitor / selective MMP-13 inhibitor / S1' specificity / no contact to Zn / Collagen degradation / Disease mutation / Disulfide bond / Extracellular matrix / Glycoprotein / Hydrolase / Metal-binding / Metalloprotease / Protease / Secreted / Zymogen / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


growth plate cartilage development / RUNX2 regulates genes involved in cell migration / endochondral ossification / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / bone morphogenesis / Assembly of collagen fibrils and other multimeric structures / bone mineralization / Activation of Matrix Metalloproteinases / response to amyloid-beta / Collagen degradation ...growth plate cartilage development / RUNX2 regulates genes involved in cell migration / endochondral ossification / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / bone morphogenesis / Assembly of collagen fibrils and other multimeric structures / bone mineralization / Activation of Matrix Metalloproteinases / response to amyloid-beta / Collagen degradation / collagen catabolic process / extracellular matrix disassembly / collagen binding / Degradation of the extracellular matrix / extracellular matrix organization / extracellular matrix / metalloendopeptidase activity / endopeptidase activity / serine-type endopeptidase activity / calcium ion binding / proteolysis / extracellular space / zinc ion binding / extracellular region
Similarity search - Function
Peptidoglycan binding-like / Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / Putative peptidoglycan binding domain / Hemopexin-like repeats / Hemopexin-like domain superfamily / Hemopexin ...Peptidoglycan binding-like / Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / Putative peptidoglycan binding domain / Hemopexin-like repeats / Hemopexin-like domain superfamily / Hemopexin / 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-3EK / Collagenase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.97 Å
AuthorsShieh, H.-S. / Collins, B. / Schnute, M.E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.
Authors: Schnute, M.E. / O'Brien, P.M. / Nahra, J. / Morris, M. / Howard Roark, W. / Hanau, C.E. / Ruminski, P.G. / Scholten, J.A. / Fletcher, T.R. / Hamper, B.C. / Carroll, J.N. / Patt, W.C. / ...Authors: Schnute, M.E. / O'Brien, P.M. / Nahra, J. / Morris, M. / Howard Roark, W. / Hanau, C.E. / Ruminski, P.G. / Scholten, J.A. / Fletcher, T.R. / Hamper, B.C. / Carroll, J.N. / Patt, W.C. / Shieh, H.S. / Collins, B. / Pavlovsky, A.G. / Palmquist, K.E. / Aston, K.W. / Hitchcock, J. / Rogers, M.D. / McDonald, J. / Johnson, A.R. / Munie, G.E. / Wittwer, A.J. / Man, C.F. / Settle, S.L. / Nemirovskiy, O. / Vickery, L.E. / Agawal, A. / Dyer, R.D. / Sunyer, T.
History
DepositionOct 26, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 10, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_site
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_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_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 / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Collagenase 3
B: Collagenase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,96514
Polymers37,5602
Non-polymers1,40512
Water10,377576
1
A: Collagenase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,4837
Polymers18,7801
Non-polymers7036
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Collagenase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,4837
Polymers18,7801
Non-polymers7036
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)120.846, 95.740, 36.443
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Collagenase 3 / / Matrix metalloproteinase-13 / MMP-13


Mass: 18779.963 Da / Num. of mol.: 2 / Fragment: catalytic domain, UNP residues 104-270
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MMP13 / Plasmid: PGEMEX1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)/PLYSS
References: UniProt: P45452, Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases
#2: Chemical
ChemComp-ZN / ZINC ION


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


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#4: Chemical ChemComp-3EK / trans-4-[(3-{2-[(4-fluorobenzyl)carbamoyl]-6-methylpyridin-4-yl}-1H-1,2,4-triazol-1-yl)methyl]cyclohexanecarboxylic acid / (1r,4r)-4-((3-(2((4-fluorobenzyl)carbamoyl)-6-methylpyridin-4-yl)-1h-1,2,4-triazol-1-yl)methyl]cyclohexanecarboxylic acid


Mass: 451.493 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H26FN5O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 576 / 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: 2.81 Å3/Da / Density % sol: 56.17 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8
Details: Protein: 5.5 mg/ml MMP-13 with 200 uM surrogate inhibitor in 20mM Tris pH 8.5 and 5 mM CaCl2. reservoir: 1.1-1.6M Li2SO4 in 0.1M Hepes pH 7.4-8.2. drop ratio: 5ul protein + 1 ul reservoir., ...Details: Protein: 5.5 mg/ml MMP-13 with 200 uM surrogate inhibitor in 20mM Tris pH 8.5 and 5 mM CaCl2. reservoir: 1.1-1.6M Li2SO4 in 0.1M Hepes pH 7.4-8.2. drop ratio: 5ul protein + 1 ul reservoir., VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-002 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Oct 13, 2005 / Details: crystal monochromator
RadiationMonochromator: crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.97→30 Å / Num. all: 30135 / Num. obs: 30135 / % possible obs: 100 % / Observed criterion σ(F): -0.5 / Observed criterion σ(I): -1 / Redundancy: 3.6 % / Biso Wilson estimate: 21.2 Å2 / Rmerge(I) obs: 0.086 / Rsym value: 0.086 / Net I/σ(I): 12.5
Reflection shellResolution: 1.97→2.04 Å / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 2.1 / Rsym value: 0.39 / % possible all: 96.2

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Processing

Software
NameVersionClassification
CrystalCleardata collection
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.97→26.14 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.934 / SU B: 6.132 / SU ML: 0.103 / Isotropic thermal model: TLS restrained individual / Cross valid method: THROUGHOUT / ESU R: 0.159 / ESU R Free: 0.147 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2176 1502 5 %RANDOM
Rwork0.17422 ---
obs0.17639 28595 97.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.065 Å2
Baniso -1Baniso -2Baniso -3
1--1.24 Å20 Å20 Å2
2--1.29 Å20 Å2
3----0.05 Å2
Refinement stepCycle: LAST / Resolution: 1.97→26.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2551 0 76 576 3203
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0212715
X-RAY DIFFRACTIONr_bond_other_d0.0010.021751
X-RAY DIFFRACTIONr_angle_refined_deg1.1361.9643693
X-RAY DIFFRACTIONr_angle_other_deg0.80434262
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7095320
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.29824.113124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.69515393
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.012154
X-RAY DIFFRACTIONr_chiral_restr0.0630.2365
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023116
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02570
X-RAY DIFFRACTIONr_nbd_refined0.1830.2594
X-RAY DIFFRACTIONr_nbd_other0.1770.21732
X-RAY DIFFRACTIONr_nbtor_refined0.1950.21316
X-RAY DIFFRACTIONr_nbtor_other0.0830.21207
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1490.2336
X-RAY DIFFRACTIONr_metal_ion_refined0.1320.215
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1270.223
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2120.255
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1650.239
X-RAY DIFFRACTIONr_mcbond_it0.4381.51634
X-RAY DIFFRACTIONr_mcbond_other0.0821.5651
X-RAY DIFFRACTIONr_mcangle_it0.71822574
X-RAY DIFFRACTIONr_scbond_it1.08531244
X-RAY DIFFRACTIONr_scangle_it1.5754.51119
LS refinement shellResolution: 1.97→2.02 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 116 -
Rwork0.258 2023 -
obs--95.19 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.47160.6937-0.31931.23520.5561.84160.0084-0.01720.0437-0.01280.01730.06980.0099-0.1211-0.0257-0.1733-0.0143-0.0082-0.20640.0146-0.211147.301729.87538.4104
24.0484-0.5561-0.97541.23320.20211.70260.11550.10160.2183-0.0789-0.0457-0.0568-0.070.0378-0.0699-0.16770.029-0.0161-0.1695-0.0297-0.138777.206432.840234.2251
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A104 - 267
2X-RAY DIFFRACTION2B104 - 267

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