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- PDB-7zyf: Insulin regulated aminopeptidase (IRAP) in complex with a nanomol... -

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Basic information

Entry
Database: PDB / ID: 7zyf
TitleInsulin regulated aminopeptidase (IRAP) in complex with a nanomolar alpha hydroxy beta amino acid based inhibitor.
ComponentsLeucyl-cystinyl aminopeptidase, pregnancy serum form
KeywordsHYDROLASE / insulin regulated aminopeptidase / IRAP / hsplap / bestatin analogues / alpla hydroxy beta amino acid based inhibitor
Function / homology
Function and homology information


cystinyl aminopeptidase / antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-independent / negative regulation of cold-induced thermogenesis / peptide catabolic process / metalloaminopeptidase activity / aminopeptidase activity / early endosome lumen / Translocation of SLC2A4 (GLUT4) to the plasma membrane / female pregnancy / Endosomal/Vacuolar pathway ...cystinyl aminopeptidase / antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-independent / negative regulation of cold-induced thermogenesis / peptide catabolic process / metalloaminopeptidase activity / aminopeptidase activity / early endosome lumen / Translocation of SLC2A4 (GLUT4) to the plasma membrane / female pregnancy / Endosomal/Vacuolar pathway / peptide binding / protein catabolic process / cytoplasmic vesicle membrane / regulation of blood pressure / protein polyubiquitination / metallopeptidase activity / Antigen processing: Ubiquitination & Proteasome degradation / cell-cell signaling / lysosomal membrane / perinuclear region of cytoplasm / signal transduction / proteolysis / extracellular space / zinc ion binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Aminopeptidase N-type / ERAP1-like C-terminal domain / ERAP1-like C-terminal domain / Aminopeptidase N-like , N-terminal domain / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase / Peptidase family M1 domain / Peptidase M1 N-terminal domain / Aminopeptidase N-like , N-terminal domain superfamliy / Peptidase M4/M1, CTD superfamily / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Chem-KFR / DI(HYDROXYETHYL)ETHER / Leucyl-cystinyl aminopeptidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.81 Å
AuthorsMpakali, A. / Stratikos, E. / Giastas, P. / Papakyriakou, A.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Union (EU)European Union
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of Selective Nanomolar Inhibitors for Insulin-Regulated Aminopeptidase Based on alpha-Hydroxy-beta-amino Acid Derivatives of Bestatin.
Authors: Vourloumis, D. / Mavridis, I. / Athanasoulis, A. / Temponeras, I. / Koumantou, D. / Giastas, P. / Mpakali, A. / Magrioti, V. / Leib, J. / van Endert, P. / Stratikos, E. / Papakyriakou, A.
History
DepositionMay 24, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 20, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 27, 2022Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Aug 10, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Leucyl-cystinyl aminopeptidase, pregnancy serum form
B: Leucyl-cystinyl aminopeptidase, pregnancy serum form
hetero molecules


Theoretical massNumber of molelcules
Total (without water)210,24137
Polymers200,2802
Non-polymers9,96135
Water1,874104
1
A: Leucyl-cystinyl aminopeptidase, pregnancy serum form
hetero molecules


Theoretical massNumber of molelcules
Total (without water)104,63817
Polymers100,1401
Non-polymers4,49816
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Leucyl-cystinyl aminopeptidase, pregnancy serum form
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,60420
Polymers100,1401
Non-polymers5,46419
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.478, 120.051, 141.246
Angle α, β, γ (deg.)90.000, 103.281, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain 'A' and (resid 158 through 186 or (resid 187...A158 - 221
121(chain 'A' and (resid 158 through 186 or (resid 187...A227 - 270
131(chain 'A' and (resid 158 through 186 or (resid 187...A273 - 338
141(chain 'A' and (resid 158 through 186 or (resid 187...A342 - 389
151(chain 'A' and (resid 158 through 186 or (resid 187...A392 - 497
161(chain 'A' and (resid 158 through 186 or (resid 187...A500 - 596
171(chain 'A' and (resid 158 through 186 or (resid 187...A600 - 637
181(chain 'A' and (resid 158 through 186 or (resid 187...A649 - 792
191(chain 'A' and (resid 158 through 186 or (resid 187...A795 - 833
1101(chain 'A' and (resid 158 through 186 or (resid 187...A836 - 1024
1111(chain 'A' and (resid 158 through 186 or (resid 187...A1026 - 1027
1121(chain 'A' and (resid 158 through 186 or (resid 187...A1033 - 1034
1131(chain 'A' and (resid 158 through 186 or (resid 187...A1044 - 1045
1141(chain 'A' and (resid 158 through 186 or (resid 187...A1048
1151(chain 'A' and (resid 158 through 186 or (resid 187...A1102
211(chain 'B' and (resid 158 or (resid 159 and (name...B158 - 221
221(chain 'B' and (resid 158 or (resid 159 and (name...B227 - 270
231(chain 'B' and (resid 158 or (resid 159 and (name...B273 - 338
241(chain 'B' and (resid 158 or (resid 159 and (name...B342 - 389
251(chain 'B' and (resid 158 or (resid 159 and (name...B392 - 497
261(chain 'B' and (resid 158 or (resid 159 and (name...B500 - 596
271(chain 'B' and (resid 158 or (resid 159 and (name...B600 - 637
281(chain 'B' and (resid 158 or (resid 159 and (name...B649 - 792
291(chain 'B' and (resid 158 or (resid 159 and (name...B795 - 833
2101(chain 'B' and (resid 158 or (resid 159 and (name...B836 - 1024
2111(chain 'B' and (resid 158 or (resid 159 and (name...B1036 - 1037
2121(chain 'B' and (resid 158 or (resid 159 and (name...B1632 - 1633
2131(chain 'B' and (resid 158 or (resid 159 and (name...B1641 - 1642
2141(chain 'B' and (resid 158 or (resid 159 and (name...B1645 - 1646

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Leucyl-cystinyl aminopeptidase, pregnancy serum form


Mass: 100139.906 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: A and B chain differ at the end regarding sugars, ZN molecule and Ligand positions
Source: (gene. exp.) Homo sapiens (human) / Gene: LNPEP, OTASE / Production host: Homo sapiens (human) / References: UniProt: Q9UIQ6

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Sugars , 5 types, 20 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#3: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 4 / Source method: obtained synthetically
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 2 / Source method: obtained synthetically
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#5: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 2 / Source method: obtained synthetically
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#7: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 6 types, 119 molecules

#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#8: Chemical ChemComp-KFR / methyl (2S)-2-[[(2S)-2-[[(2S,3R)-3-azanyl-2-oxidanyl-4-(4-oxidanylphenoxy)butanoyl]amino]-4-methyl-pentanoyl]amino]-3-(1H-indol-3-yl)propanoate / (2S-3R)-3-Amino-2-Hydroxybutyryl derivative


Mass: 540.608 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H36N4O7 / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Formula: C2H6O2
#10: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C4H10O3
#11: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C4H12NO3 / Comment: pH buffer*YM
#12: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 104 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 3.03 Å3/Da / Density % sol: 59.37 %
Crystal growTemperature: 278.15 K / Method: vapor diffusion, sitting drop / pH: 5
Details: 0.1M MMT (Malic acid, MES, Tris) 25% w/v PEG 1500 20% EG

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 0.97626 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 11, 2019
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97626 Å / Relative weight: 1
ReflectionResolution: 2.81→137.5 Å / Num. obs: 58003 / % possible obs: 99.56 % / Redundancy: 2 % / Biso Wilson estimate: 35.28 Å2 / CC1/2: 0.951 / Rmerge(I) obs: 0.1019 / Net I/σ(I): 6.56
Reflection shellResolution: 2.81→2.91 Å / Mean I/σ(I) obs: 2.62 / Num. unique obs: 5657 / CC1/2: 0.5 / % possible all: 97.92

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PHENIX1.17.1_3660refinement
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MJ6

5mj6


Resolution: 2.81→137.47 Å / SU ML: 0.4661 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 32.8531
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3143 2881 4.97 %
Rwork0.2713 55089 -
obs0.2734 57970 99.55 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.16 Å2
Refinement stepCycle: LAST / Resolution: 2.81→137.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14350 0 57 105 14512
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00514821
X-RAY DIFFRACTIONf_angle_d0.898820092
X-RAY DIFFRACTIONf_chiral_restr0.0662350
X-RAY DIFFRACTIONf_plane_restr0.00522445
X-RAY DIFFRACTIONf_dihedral_angle_d8.67542138
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.81-2.860.38881260.31822541X-RAY DIFFRACTION96.91
2.86-2.910.3911410.31062548X-RAY DIFFRACTION98.82
2.91-2.960.3281620.29132606X-RAY DIFFRACTION99.68
2.96-3.010.36111480.2962619X-RAY DIFFRACTION99.89
3.02-3.080.35761360.28942638X-RAY DIFFRACTION99.89
3.08-3.140.34781310.28522624X-RAY DIFFRACTION99.89
3.14-3.220.34041360.28452624X-RAY DIFFRACTION99.89
3.22-3.30.2891310.29532591X-RAY DIFFRACTION99.49
3.3-3.390.30861340.28772634X-RAY DIFFRACTION99.89
3.39-3.490.29351390.26922631X-RAY DIFFRACTION99.78
3.49-3.60.34041250.26792636X-RAY DIFFRACTION100
3.6-3.730.32191100.25752647X-RAY DIFFRACTION99.93
3.73-3.880.25961270.2542661X-RAY DIFFRACTION99.93
3.88-4.050.29211410.25082625X-RAY DIFFRACTION99.93
4.05-4.270.30131360.23922625X-RAY DIFFRACTION99.89
4.27-4.530.29371370.24142623X-RAY DIFFRACTION99.67
4.53-4.880.28291450.24142635X-RAY DIFFRACTION99.64
4.88-5.380.29371480.25412626X-RAY DIFFRACTION99.93
5.38-6.150.34671390.28352659X-RAY DIFFRACTION99.75
6.15-7.750.3311220.30492649X-RAY DIFFRACTION99.46
7.75-137.470.311670.29122647X-RAY DIFFRACTION98.36
Refinement TLS params.Method: refined / Origin x: 54.1781077673 Å / Origin y: -4.21193997869 Å / Origin z: 182.344213252 Å
111213212223313233
T-0.0612278717143 Å2-0.109231755683 Å2-0.0139814308733 Å2--0.241536214543 Å2-0.00111431957653 Å2---0.0309466504731 Å2
L0.34116107943 °20.0273652676352 °2-0.1726191235 °2-0.20687847558 °2-0.210418052857 °2--0.426062905585 °2
S-0.0599213401954 Å °0.0868390169694 Å °0.00972432259693 Å °0.00184720042559 Å °0.0375073897135 Å °-0.0271728108664 Å °-0.0374240198643 Å °-0.286934717407 Å °-0.237626757068 Å °
Refinement TLS groupSelection details: all

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