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- PDB-8p0i: Crystal structure of the open conformation of insulin-regulated a... -

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Basic information

Entry
Database: PDB / ID: 8p0i
TitleCrystal structure of the open conformation of insulin-regulated aminopeptidase in complex with a small-MW inhibitor
ComponentsLeucyl-cystinyl aminopeptidase, pregnancy serum form
KeywordsHYDROLASE / insulin regulated aminopeptidase / irap / hsplap / antigen presentation / 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 / cytoplasmic vesicle membrane / protein catabolic process / regulation of blood pressure / protein polyubiquitination / metallopeptidase activity / Antigen processing: Ubiquitination & Proteasome degradation / cell-cell signaling / lysosomal membrane / perinuclear region of cytoplasm / proteolysis / extracellular space / zinc ion binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Aminopeptidase N-type / ERAP1-like C-terminal domain / ERAP1-like C-terminal domain / : / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase / Aminopeptidase N-like , N-terminal domain / Peptidase family M1 domain / Peptidase M1 N-terminal domain / Aminopeptidase N-like , N-terminal domain superfamliy ...Aminopeptidase N-type / ERAP1-like C-terminal domain / ERAP1-like C-terminal domain / : / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase / Aminopeptidase N-like , N-terminal domain / 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
: / Leucyl-cystinyl aminopeptidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsMpakali, A. / Giastas, P. / Stratikos, E.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Union (EU)European Union
CitationJournal: Protein Sci. / Year: 2024
Title: Stabilization of the open conformation omicron f insulin-regulated aminopeptidase by a novel substrate-selective small-molecule inhibitor.
Authors: Mpakali, A. / Georgaki, G. / Buson, A. / Findlay, A.D. / Foot, J.S. / Mauvais, F.X. / van Endert, P. / Giastas, P. / Hamprecht, D.W. / Stratikos, E.
History
DepositionMay 10, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)209,77329
Polymers200,2802
Non-polymers9,49327
Water00
1
A: Leucyl-cystinyl aminopeptidase, pregnancy serum form
hetero molecules


Theoretical massNumber of molelcules
Total (without water)105,90816
Polymers100,1401
Non-polymers5,76815
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Leucyl-cystinyl aminopeptidase, pregnancy serum form
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,86513
Polymers100,1401
Non-polymers3,72512
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)68.229, 255.121, 73.274
Angle α, β, γ (deg.)90.000, 110.000, 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

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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
Source: (gene. exp.) Homo sapiens (human) / Gene: LNPEP, OTASE / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9UIQ6

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Sugars , 4 types, 23 molecules

#2: 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.: 4
Source method: isolated from a genetically manipulated source
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
#3: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-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.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-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_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#4: 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
#5: 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.: 13 / 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 , 2 types, 4 molecules

#6: Chemical ChemComp-WC3 / 2-[2-(3,5-dimethylpyrazol-1-yl)-6-(4-methoxyphenyl)pyrimidin-4-yl]oxy-N-methyl-N-[(2-methylpyridin-3-yl)methyl]ethanamide


Mass: 472.539 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H28N6O3 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.87 Å3/Da / Density % sol: 56.05 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 9
Details: 0.1M SPG buffer (Succinic acid, Phosphate, Glycine), pH 9.0 and 25% (w/v) polyethylene glycol (PEG)

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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: 3.5→64.11 Å / Num. obs: 29554 / % possible obs: 99.72 % / Redundancy: 2 % / Biso Wilson estimate: 117.98 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.07566 / Rpim(I) all: 0.07566 / Rrim(I) all: 0.107 / Net I/σ(I): 7.85
Reflection shellResolution: 3.5→3.5 Å / Redundancy: 2 % / Rmerge(I) obs: 0.8233 / Mean I/σ(I) obs: 1.09 / Num. unique obs: 2970 / CC1/2: 0.426 / CC star: 0.773 / Rpim(I) all: 0.8233 / Rrim(I) all: 1.164 / % possible all: 99.97

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PHENIX1.17.1_3660refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.5→64.11 Å / Cross valid method: FREE R-VALUE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2767 1689 -
Rwork0.24 --
obs-29554 99.72 %
Displacement parametersBiso mean: 117.98 Å2
Refinement stepCycle: LAST / Resolution: 3.5→64.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13314 0 622 0 13936
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007114271
X-RAY DIFFRACTIONf_angle_d1.092419458
X-RAY DIFFRACTIONf_chiral_restr0.06442336
X-RAY DIFFRACTIONf_plane_restr0.00652384
X-RAY DIFFRACTIONf_dihedral_angle_d15.67244954
LS refinement shellResolution: 3.5→3.625 Å
RfactorNum. reflection% reflection
Rfree0.3947 166 -
Rwork0.3689 2970 -
obs--99.97 %

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