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- PDB-7sh0: CRYSTAL STRUCTURE OF ENDOPLASMIC RETICULUM AMINOPEPTIDASE 2 (ERAP... -

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Basic information

Entry
Database: PDB / ID: 7sh0
TitleCRYSTAL STRUCTURE OF ENDOPLASMIC RETICULUM AMINOPEPTIDASE 2 (ERAP2) COMPLEX WITH A HIGHLY SELECTIVE AND POTENT SMALL MOLECULE
ComponentsEndoplasmic reticulum aminopeptidase 2
KeywordsIMMUNE SYSTEM / HYDROLASE/INHIBITOR / AMINOPEPTIDASE / ERAP2 STRUCTURE / ENZYME INHIBITOR / ANTIGEN PROCESSING / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


Hydrolases; Acting on peptide bonds (peptidases); Aminopeptidases / antigen processing and presentation of peptide antigen via MHC class I / peptide catabolic process / metalloaminopeptidase activity / aminopeptidase activity / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide binding / antigen processing and presentation of endogenous peptide antigen via MHC class I / regulation of blood pressure / metallopeptidase activity ...Hydrolases; Acting on peptide bonds (peptidases); Aminopeptidases / antigen processing and presentation of peptide antigen via MHC class I / peptide catabolic process / metalloaminopeptidase activity / aminopeptidase activity / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide binding / antigen processing and presentation of endogenous peptide antigen via MHC class I / regulation of blood pressure / metallopeptidase activity / endopeptidase activity / adaptive immune response / endoplasmic reticulum lumen / endoplasmic reticulum membrane / proteolysis / extracellular space / zinc ion binding / membrane / cytoplasm
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-GIY / Endoplasmic reticulum aminopeptidase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsLi, L. / Bouvier, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 AI114467 United States
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2022
Title: Discovery of the First Selective Nanomolar Inhibitors of ERAP2 by Kinetic Target-Guided Synthesis.
Authors: Camberlein, V. / Fleau, C. / Sierocki, P. / Li, L. / Gealageas, R. / Bosc, D. / Guillaume, V. / Warenghem, S. / Leroux, F. / Rosell, M. / Cheng, K. / Medve, L. / Prigent, M. / Decanter, M. / ...Authors: Camberlein, V. / Fleau, C. / Sierocki, P. / Li, L. / Gealageas, R. / Bosc, D. / Guillaume, V. / Warenghem, S. / Leroux, F. / Rosell, M. / Cheng, K. / Medve, L. / Prigent, M. / Decanter, M. / Piveteau, C. / Biela, A. / Eveque, M. / Dumont, J. / Mpakali, A. / Giastas, P. / Herledan, A. / Couturier, C. / Haupenthal, J. / Lesire, L. / Hirsch, A.K.H. / Deprez, B. / Stratikos, E. / Bouvier, M. / Deprez-Poulain, R.
History
DepositionOct 7, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 20, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 1, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 25, 2023Group: 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 2
B: Endoplasmic reticulum aminopeptidase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,32912
Polymers223,1272
Non-polymers2,20210
Water1267
1
A: Endoplasmic reticulum aminopeptidase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,7957
Polymers111,5631
Non-polymers1,2326
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Endoplasmic reticulum aminopeptidase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,5345
Polymers111,5631
Non-polymers9704
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.485, 135.949, 129.812
Angle α, β, γ (deg.)90.000, 90.490, 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-IDDetails
d_1ens_1(chain "A" and (resid 54 through 123 or resid 130...
d_2ens_1chain "B"
d_1ens_2chain "C"
d_2ens_2chain "D"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1PROGLNA1 - 70
d_12ens_1TYRLEUA77 - 446
d_13ens_1PHELEUA460 - 483
d_14ens_1GLNASPA501 - 546
d_15ens_1ASNVALA557 - 566
d_16ens_1TRPTHRA573 - 893
d_21ens_1PROTHRB1 - 841
d_11ens_2LIGLIGD
d_21ens_2LIGLIGJ

NCS ensembles :
ID
ens_1
ens_2

NCS oper: (Code: givenMatrix: (-0.99938730817, -0.01402084863, -0.0320690516157), (-0.00537706383751, 0.966883714441, -0.25516067474), (0.0345846129417, -0.254831902542, -0.966366703687)Vector: 36. ...NCS oper: (Code: given
Matrix: (-0.99938730817, -0.01402084863, -0.0320690516157), (-0.00537706383751, 0.966883714441, -0.25516067474), (0.0345846129417, -0.254831902542, -0.966366703687)
Vector: 36.7021288453, 8.61775370563, 62.795656669)

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Endoplasmic reticulum aminopeptidase 2 / Leukocyte-derived arginine aminopeptidase / L-RAP


Mass: 111563.422 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERAP2, LRAP / Plasmid: PFASTBAC-1 / Production host: Homo sapiens (human)
References: UniProt: Q6P179, Hydrolases; Acting on peptide bonds (peptidases); Aminopeptidases

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Non-polymers , 6 types, 17 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-GIY / (2S)-N-hydroxy-3-(4-methoxyphenyl)-2-[4-({[5-(pyridin-2-yl)thiophene-2-sulfonyl]amino}methyl)-1H-1,2,3-triazol-1-yl]propanamide


Mass: 514.577 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H22N6O5S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES / HEPES


Mass: 238.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#5: Chemical
ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 7 / 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: 2.99 Å3/Da / Density % sol: 58.79 %
Crystal growTemperature: 296 K / Method: vapor diffusion / pH: 6.5
Details: 12% Ethylene glycol, 6% PEG8000;0.1m MES and imidazole
PH range: 6.0-6.6

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Data collection

DiffractionMean temperature: 103 K / Ambient temp details: liguid nitrogen / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97857 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jun 2, 2021
RadiationMonochromator: 0.97857 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 3.2→20 Å / Num. obs: 42605 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Biso Wilson estimate: 103.33 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.132 / Net I/σ(I): 8.5
Reflection shellResolution: 3.2→3.39 Å / Redundancy: 3.3 % / Rmerge(I) obs: 1.2 / Mean I/σ(I) obs: 1 / Num. unique obs: 6543 / CC1/2: 0.46 / % possible all: 96

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5kiv

5kiv


Resolution: 3.2→20 Å / SU ML: 0.5645 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.6195
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2543 2163 5.08 %
Rwork0.2073 40409 -
obs0.2097 42572 99.03 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 127.4 Å2
Refinement stepCycle: LAST / Resolution: 3.2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14147 0 136 7 14290
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00214634
X-RAY DIFFRACTIONf_angle_d0.511319830
X-RAY DIFFRACTIONf_chiral_restr0.03882179
X-RAY DIFFRACTIONf_plane_restr0.00322473
X-RAY DIFFRACTIONf_dihedral_angle_d6.68991927
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AX-RAY DIFFRACTIONTorsion NCS1.58035746026
ens_2d_2AX-RAY DIFFRACTIONTorsion NCS0.0421412453952
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.2-3.280.40041220.38042524X-RAY DIFFRACTION91.46
3.28-3.360.37911400.3482676X-RAY DIFFRACTION99.93
3.36-3.450.37331540.31352718X-RAY DIFFRACTION99.86
3.45-3.550.32341700.27422672X-RAY DIFFRACTION99.82
3.55-3.670.29631540.2562675X-RAY DIFFRACTION99.75
3.67-3.80.28781320.23342714X-RAY DIFFRACTION99.75
3.8-3.950.28411370.21772719X-RAY DIFFRACTION99.79
3.95-4.120.26121390.20422711X-RAY DIFFRACTION99.86
4.12-4.340.2471360.19362713X-RAY DIFFRACTION99.79
4.34-4.610.25511420.17052718X-RAY DIFFRACTION99.62
4.61-4.960.22131710.15862690X-RAY DIFFRACTION99.76
4.96-5.450.2061310.17642715X-RAY DIFFRACTION99.34
5.45-6.220.25511420.21062725X-RAY DIFFRACTION99.45
6.22-7.760.27361320.2082730X-RAY DIFFRACTION99.13
7.76-200.19921610.17742709X-RAY DIFFRACTION98.22
Refinement TLS params.Method: refined / Origin x: 18.7670118375 Å / Origin y: 1.88376958218 Å / Origin z: 30.2391732231 Å
111213212223313233
T0.531577726982 Å2-0.053087201398 Å20.0200565323413 Å2-0.525108427502 Å20.0674237625158 Å2--0.698022678215 Å2
L1.17082471557 °2-0.311290130815 °2-0.381683865624 °2-1.8027600534 °20.421127053035 °2--2.64684952924 °2
S-0.0336121008262 Å °-0.278192303475 Å °-0.227045796722 Å °0.435086395657 Å °-0.0274098775282 Å °0.337222169829 Å °0.18835521818 Å °-0.128419554335 Å °0.0365282556835 Å °
Refinement TLS groupSelection details: all

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