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- PDB-5th9: Structure determination of a potent, selective antibody inhibitor... -

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Basic information

Entry
Database: PDB / ID: 5th9
TitleStructure determination of a potent, selective antibody inhibitor of human MMP9 (GS-5745 bound to MMP-9)
Components
  • GS-5745 Fab heavy chain
  • GS-5745 Fab light chain
  • Matrix metalloproteinase-9,Matrix metalloproteinase-9
Keywordshydrolase/hydrolase inhibitor / metalloproteinase-9 antibody inhibitor / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


gelatinase B / negative regulation of epithelial cell differentiation involved in kidney development / negative regulation of cation channel activity / negative regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / cellular response to UV-A / positive regulation of keratinocyte migration / regulation of neuroinflammatory response / positive regulation of epidermal growth factor receptor signaling pathway / Assembly of collagen fibrils and other multimeric structures / Activation of Matrix Metalloproteinases ...gelatinase B / negative regulation of epithelial cell differentiation involved in kidney development / negative regulation of cation channel activity / negative regulation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / cellular response to UV-A / positive regulation of keratinocyte migration / regulation of neuroinflammatory response / positive regulation of epidermal growth factor receptor signaling pathway / Assembly of collagen fibrils and other multimeric structures / Activation of Matrix Metalloproteinases / endodermal cell differentiation / positive regulation of release of cytochrome c from mitochondria / response to amyloid-beta / macrophage differentiation / Collagen degradation / collagen catabolic process / EPH-ephrin mediated repulsion of cells / extracellular matrix disassembly / ephrin receptor signaling pathway / positive regulation of DNA binding / negative regulation of intrinsic apoptotic signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / collagen binding / cellular response to cadmium ion / embryo implantation / Degradation of the extracellular matrix / extracellular matrix organization / positive regulation of receptor binding / skeletal system development / Signaling by SCF-KIT / metalloendopeptidase activity / cellular response to reactive oxygen species / metallopeptidase activity / cell migration / tertiary granule lumen / peptidase activity / cellular response to lipopolysaccharide / Interleukin-4 and Interleukin-13 signaling / collagen-containing extracellular matrix / endopeptidase activity / ficolin-1-rich granule lumen / Extra-nuclear estrogen signaling / positive regulation of protein phosphorylation / positive regulation of apoptotic process / serine-type endopeptidase activity / apoptotic process / Neutrophil degranulation / negative regulation of apoptotic process / proteolysis / extracellular space / zinc ion binding / extracellular exosome / extracellular region / identical protein binding
Similarity search - Function
Fibronectin type II domain / Fibronectin type II domain superfamily / Fibronectin type II domain / Fibronectin type-II collagen-binding domain signature. / Fibronectin type-II collagen-binding domain profile. / Fibronectin type 2 domain / Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidase M10A, cysteine switch, zinc binding site ...Fibronectin type II domain / Fibronectin type II domain superfamily / Fibronectin type II domain / Fibronectin type-II collagen-binding domain signature. / Fibronectin type-II collagen-binding domain profile. / Fibronectin type 2 domain / Hemopexin, conserved site / Hemopexin domain signature. / Hemopexin-like domain / Peptidase M10A, cysteine switch, zinc binding site / Matrixins cysteine switch. / 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 / Kringle-like fold / Neutral zinc metallopeptidases, zinc-binding region signature. / Immunoglobulins / Immunoglobulin-like / Sandwich / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
COBALT HEXAMMINE(III) / Matrix metalloproteinase-9
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.999 Å
AuthorsAppleby, T.C. / Greenstein, A.E. / Kwon, H.J.
CitationJournal: J. Biol. Chem. / Year: 2017
Title: Biochemical characterization and structure determination of a potent, selective antibody inhibitor of human MMP9.
Authors: Appleby, T.C. / Greenstein, A.E. / Hung, M. / Liclican, A. / Velasquez, M. / Villasenor, A.G. / Wang, R. / Wong, M.H. / Liu, X. / Papalia, G.A. / Schultz, B.E. / Sakowicz, R. / Smith, V. / Kwon, H.J.
History
DepositionSep 29, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 15, 2017Provider: repository / Type: Initial release
Revision 1.1May 3, 2017Group: Database references
Revision 1.2Oct 4, 2023Group: 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 / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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_conn.ptnr2_label_seq_id / _struct_conn_type.id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: GS-5745 Fab light chain
H: GS-5745 Fab heavy chain
A: Matrix metalloproteinase-9,Matrix metalloproteinase-9
M: GS-5745 Fab light chain
I: GS-5745 Fab heavy chain
B: Matrix metalloproteinase-9,Matrix metalloproteinase-9
N: GS-5745 Fab light chain
J: GS-5745 Fab heavy chain
C: Matrix metalloproteinase-9,Matrix metalloproteinase-9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)223,69624
Polymers222,5799
Non-polymers1,11615
Water2,522140
1
L: GS-5745 Fab light chain
H: GS-5745 Fab heavy chain
A: Matrix metalloproteinase-9,Matrix metalloproteinase-9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,5658
Polymers74,1933
Non-polymers3725
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5560 Å2
ΔGint-39 kcal/mol
Surface area27270 Å2
MethodPISA
2
M: GS-5745 Fab light chain
I: GS-5745 Fab heavy chain
B: Matrix metalloproteinase-9,Matrix metalloproteinase-9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,5658
Polymers74,1933
Non-polymers3725
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5400 Å2
ΔGint-38 kcal/mol
Surface area27240 Å2
MethodPISA
3
N: GS-5745 Fab light chain
J: GS-5745 Fab heavy chain
C: Matrix metalloproteinase-9,Matrix metalloproteinase-9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,5658
Polymers74,1933
Non-polymers3725
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3890 Å2
ΔGint-26 kcal/mol
Surface area18840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)168.167, 168.167, 234.735
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

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Protein , 1 types, 3 molecules ABC

#3: Protein Matrix metalloproteinase-9,Matrix metalloproteinase-9 / MMP-9 / 92 kDa gelatinase / 92 kDa type IV collagenase / Gelatinase B / GELB


Mass: 25962.111 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MMP9, CLG4B / Production host: Escherichia coli (E. coli) / References: UniProt: P14780, gelatinase B

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Antibody , 2 types, 6 molecules LMNHIJ

#1: Antibody GS-5745 Fab light chain


Mass: 23423.979 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Production host: Oryctolagus cuniculus (rabbit)
#2: Antibody GS-5745 Fab heavy chain


Mass: 24807.000 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Production host: Oryctolagus cuniculus (rabbit)

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Non-polymers , 4 types, 155 molecules

#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#6: Chemical ChemComp-NCO / COBALT HEXAMMINE(III)


Mass: 161.116 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: CoH18N6
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 140 / 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: 3.73 Å3/Da / Density % sol: 67.01 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: Drop: 8% (w/v) PEG 8000 0.1 M HEPES, pH 7.5 50% (v/v) Silver Bullet 21 (Hampton Research) Reservoir: 22.5% (w/v) PEG 8000 0.1 M HEPES, pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 16, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 67959 / % possible obs: 100 % / Redundancy: 6.1 % / Biso Wilson estimate: 38.93 Å2 / Rmerge(I) obs: 0.098 / Χ2: 0.971 / Net I/σ(I): 8.9 / Num. measured all: 412284
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
3-3.096.20.46555560.9311100
3.09-3.196.20.35255790.9361100
3.19-3.36.20.28356060.9661100
3.3-3.436.20.20555710.9651100
3.43-3.596.10.15455910.9391100
3.59-3.786.10.12155970.9521100
3.78-4.026.10.09156380.8731100
4.02-4.336.10.08256411.0051100
4.33-4.766.10.08456671.4441100
4.76-5.4560.0857051.3641100
5.45-6.865.80.05557640.7611100
6.86-505.80.02760440.523199.8

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
SCALEPACKdata scaling
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1L6J (MMP9), 1F8T (GS-5745 Fab)

1l6j

1f8t


Resolution: 2.999→46.641 Å / SU ML: 0.33 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.42 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.257 1999 2.95 %
Rwork0.2182 65776 -
obs0.2193 67775 99.81 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 171.53 Å2 / Biso mean: 42.7273 Å2 / Biso min: 2.27 Å2
Refinement stepCycle: final / Resolution: 2.999→46.641 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13367 0 33 140 13540
Biso mean--50.06 18.26 -
Num. residues----1717
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01313794
X-RAY DIFFRACTIONf_angle_d1.06818809
X-RAY DIFFRACTIONf_chiral_restr0.0612044
X-RAY DIFFRACTIONf_plane_restr0.0072409
X-RAY DIFFRACTIONf_dihedral_angle_d13.5278082
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.9994-3.07440.38131380.29734542468098
3.0744-3.15750.28551410.2846284769100
3.1575-3.25040.29771400.272146464786100
3.2504-3.35530.32991420.269946444786100
3.3553-3.47520.2821410.25446424783100
3.4752-3.61430.27071430.243246684811100
3.6143-3.77870.28691390.221946394778100
3.7787-3.97780.24261430.203246794822100
3.9778-4.22690.22221430.191146964839100
4.2269-4.5530.22721420.16547014843100
4.553-5.01070.19031430.160247184861100
5.0107-5.73460.20361450.176647494894100
5.7346-7.22070.26751460.219448164962100
7.2207-46.64680.25181530.232650085161100

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