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Basic information

Entry
Database: PDB / ID: 4hva
TitleMechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6
Components
  • Caspase-6
  • VEID Inhibitor
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Caspase-6 / active / VEID / uncompetitive inhibition / ternary complex / Caspase / protease / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


caspase-6 / Breakdown of the nuclear lamina / regulation of programmed cell death / positive regulation of necroptotic process / cellular response to staurosporine / : / : / TP53 Regulates Transcription of Caspase Activators and Caspases / pyroptotic inflammatory response / hepatocyte apoptotic process ...caspase-6 / Breakdown of the nuclear lamina / regulation of programmed cell death / positive regulation of necroptotic process / cellular response to staurosporine / : / : / TP53 Regulates Transcription of Caspase Activators and Caspases / pyroptotic inflammatory response / hepatocyte apoptotic process / Apoptotic cleavage of cellular proteins / protein autoprocessing / intrinsic apoptotic signaling pathway by p53 class mediator / Caspase-mediated cleavage of cytoskeletal proteins / activation of innate immune response / cysteine-type peptidase activity / epithelial cell differentiation / positive regulation of neuron apoptotic process / positive regulation of apoptotic process / cysteine-type endopeptidase activity / apoptotic process / proteolysis / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Rossmann fold - #1460 / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. / Peptidase C14A, caspase catalytic domain / Caspase, interleukin-1 beta converting enzyme (ICE) homologues / Peptidase C14, p20 domain ...Rossmann fold - #1460 / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. / Peptidase C14A, caspase catalytic domain / Caspase, interleukin-1 beta converting enzyme (ICE) homologues / Peptidase C14, p20 domain / Caspase family p20 domain profile. / : / Caspase domain / Caspase-like domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
N-[(benzyloxy)carbonyl]-L-valyl-L-alpha-glutamyl-N-[(2R)-1-carboxy-3-oxo-4-(2,3,5,6-tetrafluorophenoxy)butan-2-yl]-L-isoleucinamide / Chem-4HV / Caspase-6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.074 Å
AuthorsMurray, J.M. / Steffek, M.
CitationJournal: Plos One / Year: 2012
Title: Mechanistic and structural understanding of uncompetitive inhibitors of caspase-6.
Authors: Heise, C.E. / Murray, J. / Augustyn, K.E. / Bravo, B. / Chugha, P. / Cohen, F. / Giannetti, A.M. / Gibbons, P. / Hannoush, R.N. / Hearn, B.R. / Jaishankar, P. / Ly, C.Q. / Shah, K. / ...Authors: Heise, C.E. / Murray, J. / Augustyn, K.E. / Bravo, B. / Chugha, P. / Cohen, F. / Giannetti, A.M. / Gibbons, P. / Hannoush, R.N. / Hearn, B.R. / Jaishankar, P. / Ly, C.Q. / Shah, K. / Stanger, K. / Steffek, M. / Tang, Y. / Zhao, X. / Lewcock, J.W. / Renslo, A.R. / Flygare, J. / Arkin, M.R.
History
DepositionNov 5, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 20, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_unobs_or_zero_occ_atoms / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_value_order / _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_ref_seq_dif.details / _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

Downloads & links

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Assembly

Deposited unit
A: Caspase-6
B: Caspase-6
C: VEID Inhibitor
D: VEID Inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,3276
Polymers62,5144
Non-polymers8132
Water5,008278
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7350 Å2
ΔGint-21 kcal/mol
Surface area19070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.988, 62.647, 76.298
Angle α, β, γ (deg.)90.000, 104.790, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A and (resseq 31:175 or resseq 198:291 ) and (not element H)
21chain B and (resseq 31:175 or resseq 198:291 ) and (not element H)

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111chain A and (resseq 31:175 or resseq 198:291 ) and (not element H)A31 - 175
121chain A and (resseq 31:175 or resseq 198:291 ) and (not element H)A198 - 291
211chain B and (resseq 31:175 or resseq 198:291 ) and (not element H)B31 - 175
221chain B and (resseq 31:175 or resseq 198:291 ) and (not element H)B198 - 291

NCS oper: (Code: given
Matrix: (-0.98168, 0.123724, -0.144903), (0.126078, -0.148398, -0.980858), (-0.142859, -0.981158, 0.13008)
Vector: 6.17825, 9.97031, 9.43685)

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Components

#1: Protein Caspase-6 / CASP-6 / Apoptotic protease Mch-2 / Caspase-6 subunit p18 / Caspase-6 subunit p11


Mass: 30467.932 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP6, MCH2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P55212, caspase-6
#2: Protein/peptide VEID Inhibitor


Type: Polypeptide / Class: Inhibitor / Mass: 789.167 Da / Num. of mol.: 2 / Source method: obtained synthetically
References: N-[(benzyloxy)carbonyl]-L-valyl-L-alpha-glutamyl-N-[(2R)-1-carboxy-3-oxo-4-(2,3,5,6-tetrafluorophenoxy)butan-2-yl]-L-isoleucinamide
#3: Chemical ChemComp-4HV / N-[(2R)-1-(3-cyanophenyl)-3-hydroxypropan-2-yl]-5-(3,4-dimethoxyphenyl)furan-3-carboxamide


Mass: 406.431 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H22N2O5
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 278 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.12 Å3/Da / Density % sol: 42.07 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 4
Details: 12% PEG 3350, 0.2M NaMalonate, pH 4.0, vapor diffusion, hanging drop, temperature 289K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9786 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 16, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 2.02→50.23 Å / Num. obs: 33465 / % possible obs: 100 % / Redundancy: 3.6 % / Biso Wilson estimate: 24 Å2 / Rmerge(I) obs: 0.126 / Net I/σ(I): 14.1
Reflection shellResolution: 2.022→2.029 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.593 / Mean I/σ(I) obs: 2.4 / Num. unique all: 307 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALAdata scaling
PHASERphasing
PHENIX1.6.4_486refinement
PDB_EXTRACT3.11data extraction
HKL-2000data collection
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.074→31.785 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.23 / Cross valid method: Rfree / σ(F): 1.33 / Phase error: 21.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2135 1538 4.98 %RANDOM
Rwork0.1717 ---
obs0.1738 30877 99.24 %-
Solvent computationShrinkage radii: 1.25 Å / VDW probe radii: 1.3 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 36.595 Å2 / ksol: 0.343 e/Å3
Displacement parametersBiso max: 241.71 Å2 / Biso mean: 29.8096 Å2 / Biso min: 6.51 Å2
Baniso -1Baniso -2Baniso -3
1--4.1625 Å20 Å2-1.6761 Å2
2--3.3386 Å2-0 Å2
3---0.8239 Å2
Refinement stepCycle: LAST / Resolution: 2.074→31.785 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3949 0 60 278 4287
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0174125
X-RAY DIFFRACTIONf_angle_d1.5815556
X-RAY DIFFRACTIONf_chiral_restr0.125588
X-RAY DIFFRACTIONf_plane_restr0.007705
X-RAY DIFFRACTIONf_dihedral_angle_d15.8881576
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDTypeRms dev position (Å)
11A1931X-RAY DIFFRACTIONPOSITIONAL0.097
12B1931X-RAY DIFFRACTIONPOSITIONAL0.097
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0738-2.14070.26711210.21822483260494
2.1407-2.21720.27381240.203226922816100
2.2172-2.3060.23041450.194726662811100
2.306-2.41090.2711250.186926872812100
2.4109-2.53790.23621520.185226652817100
2.5379-2.69690.24841610.179426492810100
2.6969-2.9050.21661380.177726772815100
2.905-3.19710.22761510.171226782829100
3.1971-3.65910.21781430.159926942837100
3.6591-4.60780.16691480.145926852833100
4.6078-31.78840.17131300.16732763289399
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)
10.8930.19070.88291.6324-0.21631.0134-0.101-0.19750.1072-0.30060.1159-0.104-0.2145-0.5177-0.0220.30940.11030.0240.18010.00390.1404-12.762.89588.5849
22.331-0.9901-0.07172.1037-0.16220.2059-0.1263-0.62950.34940.280.03510.0925-0.4201-0.206-0.00640.21420.08360.02050.2532-0.15330.1302-5.16095.558738.2258
31.5507-0.2360.54761.4057-0.25413.2210.0335-0.38410.25890.11710.02090.38220.0033-0.83760.13650.22110.08190.04690.2834-0.08880.2034-15.95241.875130.415
42.0689-0.0199-0.04310.863-0.29660.1577-0.1012-0.53240.08780.348-0.026-0.03090.296-0.27560.11450.31990.02320.05080.2533-0.04040.0978-7.5135-7.966936.3739
50.4722-0.3025-0.27560.99540.49910.6829-0.1595-0.08360.23710.10850.05440.2532-0.1428-0.21750.13260.12810.0160.03090.1179-0.04610.1684-13.9056-4.692521.7315
61.71030.24060.56710.39040.04340.6505-0.01990.1321-0.1399-0.00470.01160.0212-0.0630.1029-0.02980.16740.024-0.01040.1168-0.00310.1523.4917-8.01423.4413
70.9631-0.3409-0.37131.13880.46780.768-0.0707-0.22570.19890.07550.0485-0.1067-0.2110.11520.01420.23530.00680.00350.0855-0.04610.18684.15423.759925.3504
81.88710.35290.19810.71990.36560.93340.0381-0.22790.27980.09340.0186-0.105-0.17070.1125-0.07760.24510.00750.01870.0764-0.05040.1575.83881.563526.0796
90.92880.0128-0.43371.48280.15541.04410.26460.09470.3416-0.2624-0.1669-0.1205-0.43060.1632-0.11760.2488-0.01260.06670.07640.00450.225117.8461-1.02989.3169
100.535-0.13820.48061.230.01630.845-0.03430.0158-0.0910.05620.0112-0.1410.15940.07940.00620.17620.03170.02410.045-0.01820.086210.9711-25.533814.4226
111.1539-0.77560.71341.138-0.39491.7414-0.2603-0.10640.33370.0460.0627-0.4253-0.27290.3015-00.13370.0231-0.02990.0797-0.03290.156216.1215-12.371618.8917
121.40940.2013-0.04340.4812-0.16240.6194-0.0128-0.13240.37420.1278-0.01270.1981-0.1129-0.0416-0.01220.20310.00730.0170.0923-0.00160.157-1.936-11.557819.7901
130.29240.1544-0.0360.6936-0.01760.5251-0.030.00280.0561-0.0645-0.01650.0541-0.0554-0.03870.00280.16550.01720.01690.09240.00810.0872-1.0644-14.93948.4366
141.07121.8890.66844.81180.92792.1123-0.0566-0.18110.2042-0.2932-0.35780.56090.3025-0.20670.23310.1938-0.02850.03430.1063-0.02150.1446-14.4514-24.194210.1658
150.6171-0.2679-0.05110.6661-0.16880.3099-0.06690.11910.188-0.09740.0596-0.05380.0831-0.0336-0.06270.1965-0.01250.02010.03550.01710.1049.8096-4.832410.8248
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain A and (resseq 31:44)A31 - 44
2X-RAY DIFFRACTION2chain A and (resseq 45:80)A45 - 80
3X-RAY DIFFRACTION3chain A and (resseq 81:119)A81 - 119
4X-RAY DIFFRACTION4chain A and (resseq 120:143)A120 - 143
5X-RAY DIFFRACTION5chain A and (resseq 144:161)A144 - 161
6X-RAY DIFFRACTION6chain A and (resseq 162:205)A162 - 205
7X-RAY DIFFRACTION7chain A and (resseq 206:258)A206 - 258
8X-RAY DIFFRACTION8chain A and (resseq 259:291)A259 - 291
9X-RAY DIFFRACTION9chain B and (resseq 30:44)B30 - 44
10X-RAY DIFFRACTION10chain B and (resseq 45:143)B45 - 143
11X-RAY DIFFRACTION11chain B and (resseq 144:161)B144 - 161
12X-RAY DIFFRACTION12chain B and (resseq 162:205)B162 - 205
13X-RAY DIFFRACTION13chain B and (resseq 206:258)B206 - 258
14X-RAY DIFFRACTION14chain B and (resseq 259:276)B259 - 276
15X-RAY DIFFRACTION15chain B and (resseq 277:291)B277 - 291

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