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- PDB-6f06: CATHEPSIN L IN COMPLEX WITH (3S,14E)-8-(azetidin-3-yl)-19-chloro-... -

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Basic information

Entry
Database: PDB / ID: 6f06
TitleCATHEPSIN L IN COMPLEX WITH (3S,14E)-8-(azetidin-3-yl)-19-chloro-N-(1-cyanocyclopropyl)-5-oxo-12,17-dioxa-4-azatricyclo[16.2.2.06,11]docosa-1(21),6,8,10,14,18(22),19-heptaene-3-carboxamide
ComponentsCathepsin L1
KeywordsHYDROLASE / PROTEASE INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


enkephalin processing / cathepsin L / CD4-positive, alpha-beta T cell lineage commitment / macrophage apoptotic process / chromaffin granule / elastin catabolic process / antigen processing and presentation of peptide antigen / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / endolysosome lumen / cellular response to thyroid hormone stimulus ...enkephalin processing / cathepsin L / CD4-positive, alpha-beta T cell lineage commitment / macrophage apoptotic process / chromaffin granule / elastin catabolic process / antigen processing and presentation of peptide antigen / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / endolysosome lumen / cellular response to thyroid hormone stimulus / zymogen activation / Trafficking and processing of endosomal TLR / proteoglycan binding / Assembly of collagen fibrils and other multimeric structures / cysteine-type endopeptidase activator activity involved in apoptotic process / antigen processing and presentation / protein autoprocessing / Collagen degradation / fibronectin binding / collagen catabolic process / serpin family protein binding / cysteine-type peptidase activity / endocytic vesicle lumen / Attachment and Entry / collagen binding / MHC class II antigen presentation / Degradation of the extracellular matrix / multivesicular body / lysosomal lumen / proteolysis involved in protein catabolic process / Endosomal/Vacuolar pathway / positive regulation of apoptotic signaling pathway / antigen processing and presentation of exogenous peptide antigen via MHC class II / histone binding / collagen-containing extracellular matrix / adaptive immune response / receptor-mediated endocytosis of virus by host cell / lysosome / Attachment and Entry / immune response / symbiont entry into host cell / apical plasma membrane / cysteine-type endopeptidase activity / fusion of virus membrane with host plasma membrane / intracellular membrane-bounded organelle / fusion of virus membrane with host endosome membrane / Golgi apparatus / proteolysis / extracellular space / extracellular exosome / extracellular region / nucleus / plasma membrane
Similarity search - Function
Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Papain-like cysteine endopeptidase / Cysteine peptidase, asparagine active site / Eukaryotic thiol (cysteine) proteases asparagine active site. / Cysteine peptidase, histidine active site / Eukaryotic thiol (cysteine) proteases histidine active site. / : / Peptidase C1A, papain C-terminal ...Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Cathepsin propeptide inhibitor domain (I29) / Papain-like cysteine endopeptidase / Cysteine peptidase, asparagine active site / Eukaryotic thiol (cysteine) proteases asparagine active site. / Cysteine peptidase, histidine active site / Eukaryotic thiol (cysteine) proteases histidine active site. / : / Peptidase C1A, papain C-terminal / Papain family cysteine protease / Papain family cysteine protease / Cysteine proteinases / Cysteine peptidase, cysteine active site / Eukaryotic thiol (cysteine) proteases cysteine active site. / Cathepsin B; Chain A / Papain-like cysteine peptidase superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-C7T / Procathepsin L
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.02 Å
AuthorsKuglstatter, A. / Stihle, M.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.
Authors: Giroud, M. / Dietzel, U. / Anselm, L. / Banner, D. / Kuglstatter, A. / Benz, J. / Blanc, J.B. / Gaufreteau, D. / Liu, H. / Lin, X. / Stich, A. / Kuhn, B. / Schuler, F. / Kaiser, M. / Brun, R. ...Authors: Giroud, M. / Dietzel, U. / Anselm, L. / Banner, D. / Kuglstatter, A. / Benz, J. / Blanc, J.B. / Gaufreteau, D. / Liu, H. / Lin, X. / Stich, A. / Kuhn, B. / Schuler, F. / Kaiser, M. / Brun, R. / Schirmeister, T. / Kisker, C. / Diederich, F. / Haap, W.
History
DepositionNov 17, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 11, 2018Provider: repository / Type: Initial release
Revision 1.1May 9, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cathepsin L1
B: Cathepsin L1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,38420
Polymers48,3832
Non-polymers2,00118
Water1,76598
1
A: Cathepsin L1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1279
Polymers24,1921
Non-polymers9358
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cathepsin L1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,25711
Polymers24,1921
Non-polymers1,06610
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.040, 50.791, 84.911
Angle α, β, γ (deg.)90.00, 91.53, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Cathepsin L1 / Cathepsin L / Major excreted protein / MEP


Mass: 24191.701 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CTSL, CTSL1 / Production host: Escherichia coli (E. coli) / References: UniProt: P07711, cathepsin L
#2: Chemical ChemComp-C7T / (3~{S},14~{E})-8-(azetidin-3-yl)-19-chloranyl-~{N}-(1-cyanocyclopropyl)-5-oxidanylidene-12,17-dioxa-4-azatricyclo[16.2.2.0^{6,11}]docosa-1(21),6(11),7,9,14,18(22),19-heptaene-3-carboxamide


Mass: 506.981 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H27ClN4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 98 / 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: 1.92 Å3/Da / Density % sol: 35.85 %
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 20% PEG3350, 0.05 M zinc acetate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 21, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.02→42.48 Å / Num. obs: 22641 / % possible obs: 98.3 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.127 / Net I/σ(I): 5.7
Reflection shellResolution: 2.02→2.07 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.873 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 1747 / % possible all: 98.9

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Processing

Software
NameVersionClassification
REFMAC5.7.0027refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementResolution: 2.02→42.48 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.915 / SU B: 11.785 / SU ML: 0.176 / Cross valid method: THROUGHOUT / ESU R: 0.271 / ESU R Free: 0.225
RfactorNum. reflection% reflectionSelection details
Rfree0.27428 1220 5.1 %RANDOM
Rwork0.20118 ---
obs0.20489 22641 98.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 33.514 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å20 Å2-0.26 Å2
2---0.38 Å20 Å2
3---0.32 Å2
Refinement stepCycle: 1 / Resolution: 2.02→42.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3372 0 88 98 3558
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0193541
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.7591.9644799
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9115434
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.52125.148169
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.72415546
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.341512
X-RAY DIFFRACTIONr_chiral_restr0.1110.2472
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212792
X-RAY DIFFRACTIONr_gen_planes_other
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.02→2.072 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.378 87 -
Rwork0.285 1660 -
obs--98.87 %
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)
11.3931-0.0142-0.84211.10360.10462.78050.01190.0036-0.0086-0.004-0.00150.04590.126-0.0871-0.01040.01320.012-0.00310.0584-0.00040.1063-4.3955-3.5074-12.3493
21.1278-0.2739-0.03111.92870.58371.7443-0.088-0.1378-0.05660.1390.0937-0.00970.22810.0434-0.00570.09440.00580.01940.04120.00210.0748-24.7926-22.3641-29.7264
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 220
2X-RAY DIFFRACTION2B1 - 220

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