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- PDB-4pes: Crystal structure of insulin degrading enzyme complexed with inhi... -

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Basic information

Entry
Database: PDB / ID: 4pes
TitleCrystal structure of insulin degrading enzyme complexed with inhibitor tert-butyl [(2S)-2-(2,5-difluorophenyl)-3-(quinolin-3-yl)propyl]carbamate
Components
  • Ala-Ala-Ala
  • Insulin-degrading enzyme
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


insulysin / beta-endorphin binding / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / cytosolic proteasome complex / insulin binding ...insulysin / beta-endorphin binding / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / cytosolic proteasome complex / insulin binding / regulation of aerobic respiration / peptide catabolic process / amyloid-beta clearance / peroxisomal matrix / amyloid-beta metabolic process / positive regulation of protein binding / Insulin receptor recycling / negative regulation of proteolysis / peptide binding / proteolysis involved in protein catabolic process / Peroxisomal protein import / protein catabolic process / antigen processing and presentation of endogenous peptide antigen via MHC class I / metalloendopeptidase activity / positive regulation of protein catabolic process / insulin receptor signaling pathway / peroxisome / amyloid-beta binding / virus receptor activity / endopeptidase activity / basolateral plasma membrane / Ub-specific processing proteases / external side of plasma membrane / protein-containing complex binding / cell surface / protein homodimerization activity / ATP hydrolysis activity / mitochondrion / proteolysis / extracellular space / extracellular exosome / zinc ion binding / ATP binding / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / : / PQQ synthase PqqF-like, C-terminal lobe domain 4 / : / Cytochrome Bc1 Complex; Chain A, domain 1 / Metalloenzyme, LuxS/M16 peptidase-like / Peptidase M16, zinc-binding site / Insulinase family, zinc-binding region signature. / Peptidase M16, C-terminal ...Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / : / PQQ synthase PqqF-like, C-terminal lobe domain 4 / : / Cytochrome Bc1 Complex; Chain A, domain 1 / Metalloenzyme, LuxS/M16 peptidase-like / Peptidase M16, zinc-binding site / Insulinase family, zinc-binding region signature. / Peptidase M16, C-terminal / Peptidase M16 inactive domain / Peptidase M16, N-terminal / Insulinase (Peptidase family M16) / Metalloenzyme, LuxS/M16 peptidase-like / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-2PJ / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.21 Å
AuthorsWang, Y. / Guo, S.
CitationJournal: To Be Published
Title: Crystal structure of IDE complexed with an inhibitor
Authors: Durham, T.B. / Toth, J.L. / Klimkowski, V.J. / Cao, J.X.C. / Siesky, A.M. / Alexander-Chacko, J. / Wu, G.Y. / Dixon, J.T. / McGee, J.E. / Wang, Y. / Guo, S. / Cavitt, R.N. / Schindler, J. / ...Authors: Durham, T.B. / Toth, J.L. / Klimkowski, V.J. / Cao, J.X.C. / Siesky, A.M. / Alexander-Chacko, J. / Wu, G.Y. / Dixon, J.T. / McGee, J.E. / Wang, Y. / Guo, S. / Cavitt, R.N. / Schindler, J. / Thibodeaux, S.J. / Calvert, N.A. / Coghlan, M.J. / Sindelar, D.K. / Christe, M. / Kiselyov, V.V. / Dodson, M. / Sloop, K.W.
History
DepositionApr 24, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2015Provider: repository / Type: Initial release
Revision 2.0Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Non-polymer description / Other / Refinement description / Source and taxonomy / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_assembly / pdbx_struct_conn_angle / pdbx_struct_oper_list / refine_hist / struct_ncs_dom_lim
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_ligand / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Insulin-degrading enzyme
B: Insulin-degrading enzyme
C: Ala-Ala-Ala
D: Ala-Ala-Ala
hetero molecules


Theoretical massNumber of molelcules
Total (without water)230,3778
Polymers229,4494
Non-polymers9284
Water8,503472
1
A: Insulin-degrading enzyme
C: Ala-Ala-Ala
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,1894
Polymers114,7252
Non-polymers4642
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area520 Å2
ΔGint-38 kcal/mol
Surface area40160 Å2
MethodPISA
2
B: Insulin-degrading enzyme
D: Ala-Ala-Ala
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,1894
Polymers114,7252
Non-polymers4642
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area520 Å2
ΔGint-37 kcal/mol
Surface area40610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.754, 116.087, 123.923
Angle α, β, γ (deg.)90.00, 98.09, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: ASN / Beg label comp-ID: ASN / End auth comp-ID: ILE / End label comp-ID: ILE / Refine code: _ / Auth seq-ID: 44 - 1012 / Label seq-ID: 14 - 982

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein Insulin-degrading enzyme / Abeta-degrading protease / Insulin protease / Insulinase / Insulysin


Mass: 114493.484 Da / Num. of mol.: 2 / Fragment: UNP residues 42-1019
Mutation: C110L, E111Q, C171S, C178A, C257V, C414L, C573N, C590S, C789S, C812A, C819A, C904S, C966N, C974A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDE / Production host: Escherichia coli (E. coli) / References: UniProt: P14735, insulysin
#2: Protein/peptide Ala-Ala-Ala


Mass: 231.249 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Chemical ChemComp-2PJ / tert-butyl [(2S)-2-(2,5-difluorophenyl)-3-(quinolin-3-yl)propyl]carbamate


Mass: 398.446 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H24F2N2O2
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 472 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.44 Å3/Da / Density % sol: 49.68 %
Crystal growTemperature: 298 K / Method: vapor diffusion / Details: 20% PEG3350, 0.2 mM sodium thiocyanate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97931 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Oct 12, 2011
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 2.2→122.69 Å / Num. obs: 119894 / % possible obs: 98.8 % / Redundancy: 3.7 % / Rsym value: 0.07 / Net I/σ(I): 7.9
Reflection shellHighest resolution: 2.2 Å / Rsym value: 0.606

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
SCALAdata scaling
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2G47

2g47


Resolution: 2.21→122.69 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.93 / SU B: 8.065 / SU ML: 0.194 / Cross valid method: THROUGHOUT / ESU R: 0.285 / ESU R Free: 0.221 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25606 1008 0.9 %RANDOM
Rwork0.20884 ---
obs0.20926 107879 98.63 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 46.756 Å2
Baniso -1Baniso -2Baniso -3
1-3.22 Å20 Å20.73 Å2
2---0.82 Å20 Å2
3----2.19 Å2
Refinement stepCycle: 1 / Resolution: 2.21→122.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15660 0 60 472 16192
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0216127
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3311.96921829
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.26951918
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.12324.531799
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.826152863
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.051582
X-RAY DIFFRACTIONr_chiral_restr0.0910.22345
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02112381
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
Refine LS restraints NCS

Ens-ID: 1 / Number: 1218 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.09 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.21→2.267 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.471 75 -
Rwork0.399 7514 -
obs--94.67 %

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