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- PDB-4cde: Human DPP1 in complex with 4-amino-N-((1S)-1-cyano-2-(4-(4- cyano... -

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Basic information

Entry
Database: PDB / ID: 4cde
TitleHuman DPP1 in complex with 4-amino-N-((1S)-1-cyano-2-(4-(4- cyanophenyl)phenyl)ethyl)tetrahydropyran-4-carboxamide
Components(DIPEPTIDYL PEPTIDASE 1 ...Cathepsin C) x 3
KeywordsHYDROLASE / DPP1 / INHIBITOR
Function / homology
Function and homology information


COPII-mediated vesicle transport / MHC class II antigen presentation / Cargo concentration in the ER / Neutrophil degranulation / dipeptidyl-peptidase I / peptidase activator activity involved in apoptotic process / negative regulation of myelination / positive regulation of proteolysis involved in cellular protein catabolic process / T cell mediated cytotoxicity / COPII vesicle coating ...COPII-mediated vesicle transport / MHC class II antigen presentation / Cargo concentration in the ER / Neutrophil degranulation / dipeptidyl-peptidase I / peptidase activator activity involved in apoptotic process / negative regulation of myelination / positive regulation of proteolysis involved in cellular protein catabolic process / T cell mediated cytotoxicity / COPII vesicle coating / positive regulation of apoptotic signaling pathway / COPII-coated ER to Golgi transport vesicle / positive regulation of microglial cell activation / chloride ion binding / phosphatase binding / response to organic substance / cysteine-type peptidase activity / endoplasmic reticulum-Golgi intermediate compartment membrane / proteolysis involved in cellular protein catabolic process / protein self-association / azurophil granule lumen / chaperone binding / endoplasmic reticulum to Golgi vesicle-mediated transport / collagen-containing extracellular matrix / cysteine-type endopeptidase activity / lysosome / immune response / aging / centrosome / intracellular membrane-bounded organelle / Golgi membrane / endoplasmic reticulum lumen / proteolysis / serine-type endopeptidase activity / neutrophil degranulation / extracellular space / extracellular exosome / membrane / nucleoplasm / extracellular region / identical protein binding
Cathepsin C exclusion domain / Cysteine peptidase, asparagine active site / Eukaryotic thiol (cysteine) proteases asparagine active site. / Eukaryotic thiol (cysteine) proteases histidine active site. / Cysteine peptidase, cysteine active site / Peptidase C1A, papain C-terminal / Cathepsin C exclusion / Cysteine peptidase, histidine active site / Cathepsin C, exclusion domain superfamily / Papain-like cysteine peptidase superfamily ...Cathepsin C exclusion domain / Cysteine peptidase, asparagine active site / Eukaryotic thiol (cysteine) proteases asparagine active site. / Eukaryotic thiol (cysteine) proteases histidine active site. / Cysteine peptidase, cysteine active site / Peptidase C1A, papain C-terminal / Cathepsin C exclusion / Cysteine peptidase, histidine active site / Cathepsin C, exclusion domain superfamily / Papain-like cysteine peptidase superfamily / Cathepsin C / Papain family cysteine protease / Eukaryotic thiol (cysteine) proteases cysteine active site.
Dipeptidyl peptidase 1
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsDebreczeni, J. / Edman, K. / Furber, M. / Tiden, A. / Gardiner, P. / Mete, T. / Ford, R. / Millichip, I. / Stein, L. / Mather, A. / Kinchin, E. / Luckhurst, C. / Cage, P. / Sanghanee, H. / Breed, J. / Wissler, L.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Cathepsin C Inhibitors: Property Optimization and Identification of a Clinical Candidate.
Authors: Furber, M. / Gardiner, P. / Tiden, A.K. / Mete, A. / Ford, R. / Millichip, I. / Stein, L. / Mather, A. / Kinchin, E. / Luckhurst, C. / Barber, S. / Cage, P. / Sanganee, H. / Austin, R. / Chohan, K. / Beri, R. / Thong, B. / Wallace, A. / Oreffo, V. / Hutchinson, R. / Harper, S. / Debreczeni, J. / Breed, J. / Wissler, L. / Edman, K.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Oct 31, 2013 / Release: Mar 19, 2014
RevisionDateData content typeGroupCategoryItemProviderType
1.0Mar 19, 2014Structure modelrepositoryInitial release
1.1Apr 9, 2014Structure modelDatabase references
1.2Mar 29, 2017Structure modelOther
1.3Apr 24, 2019Structure modelData collection / Derived calculations / Source and taxonomyentity_src_gen / struct_conn_entity_src_gen.pdbx_host_org_cell_line / _struct_conn.pdbx_leaving_atom_flag
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AA" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 8-STRANDED BARREL THIS IS REPRESENTED BY A 9-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "DA" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 8-STRANDED BARREL THIS IS REPRESENTED BY A 9-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DIPEPTIDYL PEPTIDASE 1 EXCLUSION DOMAIN CHAIN
B: DIPEPTIDYL PEPTIDASE 1 HEAVY CHAIN
C: DIPEPTIDYL PEPTIDASE 1 LIGHT CHAIN
D: DIPEPTIDYL PEPTIDASE 1 EXCLUSION DOMAIN CHAIN
E: DIPEPTIDYL PEPTIDASE 1 HEAVY CHAIN
F: DIPEPTIDYL PEPTIDASE 1 LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,13614
Polymers79,4276
Non-polymers1,7098
Water2,558142
1
D: DIPEPTIDYL PEPTIDASE 1 EXCLUSION DOMAIN CHAIN
E: DIPEPTIDYL PEPTIDASE 1 HEAVY CHAIN
F: DIPEPTIDYL PEPTIDASE 1 LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5687
Polymers39,7143
Non-polymers8544
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9220 Å2
ΔGint-66.5 kcal/mol
Surface area14960 Å2
MethodPISA
2
A: DIPEPTIDYL PEPTIDASE 1 EXCLUSION DOMAIN CHAIN
B: DIPEPTIDYL PEPTIDASE 1 HEAVY CHAIN
C: DIPEPTIDYL PEPTIDASE 1 LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5687
Polymers39,7143
Non-polymers8544
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10070 Å2
ΔGint-55.8 kcal/mol
Surface area15700 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)84.350, 84.350, 224.940
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

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DIPEPTIDYL PEPTIDASE 1 ... , 3 types, 6 molecules ADBECF

#1: Protein/peptide DIPEPTIDYL PEPTIDASE 1 EXCLUSION DOMAIN CHAIN / DIPEPTIDYL PEPTIDASE I EXCLUSION DOMAIN CHAIN / CATHEPSIN C / CATHEPSIN J / DIPEPTIDYL PEPTIDASE I / DPP-I / DPPI / DIPEPTIDYL TRANSFERASE


Mass: 13500.163 Da / Num. of mol.: 2 / Fragment: DPP1 EXCLUSION DOMAIN, RESIDUES 25-143
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P53634, dipeptidyl-peptidase I
#2: Protein/peptide DIPEPTIDYL PEPTIDASE 1 HEAVY CHAIN / Cathepsin C / DIPEPTIDYL PEPTIDASE I HEAVY CHAIN / CATHEPSIN C / CATHEPSIN J / DIPEPTIDYL PEPTIDASE I / DPP-I / DPPI / DIPEPTIDYL TRANSFERASE


Mass: 18630.018 Da / Num. of mol.: 2 / Fragment: DPP1 HEAVY CHAIN, RESIDUES 230-394
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P53634, dipeptidyl-peptidase I
#3: Protein/peptide DIPEPTIDYL PEPTIDASE 1 LIGHT CHAIN / Cathepsin C / DIPEPTIDYL PEPTIDASE I LIGHT CHAIN / CATHEPSIN C / CATHEPSIN J / DIPEPTIDYL PEPTIDASE I / DPP-I / DPPI / DIPEPTIDYL TRANSFERASE


Mass: 7583.444 Da / Num. of mol.: 2 / Fragment: DPP1 LIGHT CHAIN, RESIDUES 371-439
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P53634, dipeptidyl-peptidase I

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Non-polymers , 4 types, 150 molecules

#4: Chemical
ChemComp-NAG / N-ACETYL-D-GLUCOSAMINE


Mass: 221.208 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6 / N-Acetylglucosamine
#5: Chemical ChemComp-U6B / 4-AZANYL-N-[(2S)-1-AZANYLIDENE-3-[4-(4-CYANOPHENYL)PHENYL]PROPAN-2-YL]OXANE-4-CARBOXAMIDE


Mass: 376.452 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24N4O2
#6: Chemical ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 142 / Source method: isolated from a natural source / Formula: H2O / Water

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Details

Nonpolymer detailsN-ACETYL-D-GLUCOSAMINE (NAG): POSTTRANSLATIONAL MODIFICATION

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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: 2.91 Å3/Da / Density % sol: 57.71 % / Description: NONE
Crystal growDetails: 21% PEG3350, 200MM AMSO4, 100MM NA ACETATE PH 4.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Type: ESRF / Wavelength: 0.97
DetectorDetector: CCD / Date: Feb 19, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.4→42.17 Å / Num. obs: 37102 / % possible obs: 99.7 % / Observed criterion σ(I): 2 / Redundancy: 5.88 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 5.8
Reflection shellResolution: 2.4→2.53 Å / Redundancy: 5.68 % / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 2.35 / % possible all: 99.7

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1K3B
Resolution: 2.4→20 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.924 / SU B: 14.853 / SU ML: 0.176 / Cross valid method: THROUGHOUT / ESU R: 0.326 / ESU R Free: 0.239 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.24174 1851 5 %RANDOM
Rwork0.19359 ---
Obs0.19592 35217 99.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 67.142 Å2
Baniso -1Baniso -2Baniso -3
1--0.91 Å2-0.91 Å20 Å2
2---0.91 Å20 Å2
3---2.94 Å2
Refinement stepCycle: LAST / Resolution: 2.4→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5471 0 114 142 5727
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal targetNumber
r_bond_refined_d0.0080.0195803
r_bond_other_d0.0010.025175
r_angle_refined_deg1.2491.9457886
r_angle_other_deg0.733.00411861
r_dihedral_angle_1_deg6.2395689
r_dihedral_angle_2_deg31.68123.824272
r_dihedral_angle_3_deg13.61215866
r_dihedral_angle_4_deg19.6191522
r_chiral_restr0.070.2809
r_gen_planes_refined0.0050.026663
r_gen_planes_other0.0010.021465
r_nbd_refined
r_nbd_other
r_nbtor_refined
r_nbtor_other
r_xyhbond_nbd_refined
r_xyhbond_nbd_other
r_metal_ion_refined
r_metal_ion_other
r_symmetry_vdw_refined
r_symmetry_vdw_other
r_symmetry_hbond_refined
r_symmetry_hbond_other
r_symmetry_metal_ion_refined
r_symmetry_metal_ion_other
r_mcbond_it2.0164.3612768
r_mcbond_other2.0144.362767
r_mcangle_it3.167.3463453
r_mcangle_other
r_scbond_it2.554.7333034
r_scbond_other
r_scangle_it
r_scangle_other
r_long_range_B_refined
r_long_range_B_other
r_rigid_bond_restr
r_sphericity_free
r_sphericity_bonded
LS refinement shellResolution: 2.4→2.461 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 122 -
Rwork0.267 2508 -
Obs--99.89 %
Refinement TLS params.

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

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
12.32950.7982-0.68082.6671-0.51270.88290.0881-0.023-0.555-0.1426-0.2502-0.54120.29030.24860.1620.42650.1513-0.07360.13220.03520.399924.976445.569177.0545
22.29790.14220.1353.2055-0.41930.69230.02870.0661-0.3432-0.23150.10280.70910.2686-0.1419-0.13150.3077-0.115-0.15960.07190.00230.44530.58350.908274.352
31.6551-0.09480.28032.5788-0.29291.89530.0986-0.171-0.33440.22610.06890.79430.238-0.213-0.16750.2501-0.11280.00230.08140.03950.4633-1.964254.073684.2542
44.09851.0151-0.89433.5994-0.67431.85940.05260.8661-0.0722-1.02280.03210.38880.2743-0.3791-0.08470.6890.0465-0.1310.3947-0.06890.060110.890869.098648.1587
52.4085-0.1308-0.17862.5557-0.41880.87290.10650.5354-0.2653-0.6611-0.2398-0.80070.25830.29260.13320.48120.2110.27750.35170.01880.316435.459367.501653.3808
62.3665-0.51020.77894.4616-0.51431.26720.02770.51720.1149-0.619-0.1693-1.00330.02640.42120.14160.34070.0880.30.29610.08560.330938.088877.787554.7702
Refinement TLS group

Refinement-ID: X-RAY DIFFRACTION

IDRefine TLS-IDAuth asym-IDAuth seq-ID
11A1 - 119
22B206 - 370
33C371 - 439
44D1 - 119
55E206 - 369
66F371 - 439

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