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- PDB-7z28: High-resolution crystal structure of ERAP1 with bound bestatin an... -

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Basic information

Entry
Database: PDB / ID: 7z28
TitleHigh-resolution crystal structure of ERAP1 with bound bestatin analogue inhibitor
ComponentsEndoplasmic reticulum aminopeptidase 1
KeywordsHYDROLASE / Erap1 / Aminopeptidase / Zinc / metallopeptidase / bestatin / bestatin analogue / inhibitor
Function / homology
Function and homology information


interleukin-1, type II receptor binding / interleukin-6 receptor binding / Hydrolases; Acting on peptide bonds (peptidases); Aminopeptidases / antigen processing and presentation of peptide antigen via MHC class I / metalloexopeptidase activity / peptide catabolic process / regulation of innate immune response / fat cell differentiation / metalloaminopeptidase activity / membrane protein ectodomain proteolysis ...interleukin-1, type II receptor binding / interleukin-6 receptor binding / Hydrolases; Acting on peptide bonds (peptidases); Aminopeptidases / antigen processing and presentation of peptide antigen via MHC class I / metalloexopeptidase activity / peptide catabolic process / regulation of innate immune response / fat cell differentiation / metalloaminopeptidase activity / membrane protein ectodomain proteolysis / aminopeptidase activity / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide binding / response to bacterium / antigen processing and presentation of endogenous peptide antigen via MHC class I / regulation of blood pressure / positive regulation of angiogenesis / angiogenesis / adaptive immune response / endopeptidase activity / endoplasmic reticulum lumen / endoplasmic reticulum membrane / endoplasmic reticulum / proteolysis / extracellular space / zinc ion binding / extracellular exosome / extracellular region / 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-I88 / D-MALATE / TRIETHYLENE GLYCOL / Endoplasmic reticulum aminopeptidase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsGiastas, P. / Papakyriakou, A. / Stratikos, E. / Vourloumis, D.
Funding support Greece, 1items
OrganizationGrant numberCountry
Hellenic Foundation for Research and Innovation (HFRI) Greece
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
DepositionFeb 26, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 10, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 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: Endoplasmic reticulum aminopeptidase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,98525
Polymers98,4051
Non-polymers2,58024
Water15,889882
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5350 Å2
ΔGint77 kcal/mol
Surface area31930 Å2
Unit cell
Length a, b, c (Å)57.651, 113.174, 140.165
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Endoplasmic reticulum aminopeptidase 1 / ARTS-1 / Adipocyte-derived leucine aminopeptidase / A-LAP / Aminopeptidase PILS / Puromycin- ...ARTS-1 / Adipocyte-derived leucine aminopeptidase / A-LAP / Aminopeptidase PILS / Puromycin-insensitive leucyl-specific aminopeptidase / PILS-AP / Type 1 tumor necrosis factor receptor shedding aminopeptidase regulator


Mass: 98405.336 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Bestatin analogue inhibitor / Source: (gene. exp.) Homo sapiens (human) / Gene: ERAP1, APPILS, ARTS1, KIAA0525, UNQ584/PRO1154
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q9NZ08, Hydrolases; Acting on peptide bonds (peptidases); Aminopeptidases

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Sugars , 2 types, 2 molecules

#2: 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.: 1
Source method: isolated from a genetically manipulated source
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
#3: 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.: 1 / 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, 904 molecules

#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-I88 / methyl (2~{S})-2-[[(2~{S})-2-[[(2~{S},3~{R})-3-azanyl-2,7-bis(oxidanyl)heptanoyl]amino]-4-methyl-pentanoyl]amino]-3-(4-hydroxyphenyl)propanoate


Mass: 467.556 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H37N3O7 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 18 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical ChemComp-MLT / D-MALATE / (2R)-2-HYDROXYBUTANEDIOIC ACID / 2-HYDROXY-SUCCINIC ACID


Mass: 134.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O5
#8: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 882 / 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: 2.32 Å3/Da / Density % sol: 47.06 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / Details: 0.1 M SPG 7.0 25 % w/v PEG 1500

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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: 0.987 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 6, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.55→88.05 Å / Num. obs: 132999 / % possible obs: 99.61 % / Observed criterion σ(F): 1.33 / Redundancy: 12 % / CC1/2: 0.75 / Rmerge(I) obs: 0.089 / Net I/σ(I): 17.2
Reflection shellResolution: 1.55→1.57 Å / Rmerge(I) obs: 0.654 / Num. unique obs: 4161 / CC1/2: 0.75

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6Q4R

6q4r


Resolution: 1.55→88.05 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 18.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1822 6621 4.98 %
Rwork0.1649 126378 -
obs0.1658 132999 99.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 91.65 Å2 / Biso mean: 24.1324 Å2 / Biso min: 11.25 Å2
Refinement stepCycle: final / Resolution: 1.55→88.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6905 0 293 882 8080
Biso mean--39.71 33.11 -
Num. residues----859
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.55-1.570.34672190.319241614380100
1.57-1.590.34791970.291341814378100
1.59-1.610.28292180.271641754393100
1.61-1.630.29662080.256141854393100
1.63-1.650.27532150.252442254440100
1.65-1.670.23662000.233641664366100
1.67-1.690.22342050.212941904395100
1.69-1.720.23331970.201941874384100
1.72-1.750.23312330.193242044437100
1.75-1.770.24742250.195941184343100
1.77-1.80.23472090.194142184427100
1.8-1.840.2222220.194641804402100
1.84-1.870.22372280.186141994427100
1.87-1.910.18962070.173441924399100
1.91-1.950.20312120.160741974409100
1.95-20.18772300.155542124442100
2-2.050.18162010.157842394440100
2.05-2.10.20322170.15641704387100
2.1-2.170.18442190.15242084427100
2.17-2.240.17112290.149541934422100
2.24-2.320.172300.15364198442899
2.32-2.410.18542200.156142334453100
2.41-2.520.20622070.155642404447100
2.52-2.650.16752060.1642494455100
2.65-2.820.19162260.159542404466100
2.82-3.030.16862450.164142234468100
3.03-3.340.18532320.15324206443898
3.34-3.820.1412330.14254250448399
3.82-4.820.1472620.13044295455799
4.82-88.050.15342690.16974444471398
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)
10.5047-0.0223-0.17660.34030.07190.88380.03310.08010.0065-0.0359-0.0110.00190.0341-0.0652-0.02110.13290.00690.00630.13060.00880.1294589.202-310.3715577.2317
21.0266-0.3475-1.13770.33650.41081.66340.11530.00530.1569-0.0837-0.0226-0.0915-0.1429-0.0467-0.04470.1520.03390.01370.13930.020.1922571.5497-290.0289599.5721
30.7311-0.1754-0.23980.41610.15530.609-0.0426-0.0831-0.03240.04710.0464-0.03110.11780.076-0.00290.12680.0198-0.0080.12720.01540.1242592.1834-311.238610.7434
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 45 through 468 )A45 - 468
2X-RAY DIFFRACTION2chain 'A' and (resid 469 through 590 )A469 - 590
3X-RAY DIFFRACTION3chain 'A' and (resid 591 through 936 )A591 - 936

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