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- PDB-5mj6: Ligand-induced conformational change of Insulin-regulated aminope... -

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Basic information

Entry
Database: PDB / ID: 5mj6
TitleLigand-induced conformational change of Insulin-regulated aminopeptidase: insights on catalytic mechanism and active site plasticity.
ComponentsLeucyl-cystinyl aminopeptidase
KeywordsHYDROLASE / Insulin-regulated aminopeptidase / Endoplasmatic Reticulum Aminopeptidases / generation of antigenic peptides for cross-presentation / phosphinic pseudotripeptides / ligand-induced conformational changes
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
Zincin-like fold - #20 / Immunoglobulin-like - #1910 / Aminopeptidase N-type / ERAP1-like C-terminal domain / ERAP1-like C-terminal domain / Zincin-like fold / tricorn interacting facor f3 domain / Aminopeptidase N-like , N-terminal domain / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase ...Zincin-like fold - #20 / Immunoglobulin-like - #1910 / Aminopeptidase N-type / ERAP1-like C-terminal domain / ERAP1-like C-terminal domain / Zincin-like fold / tricorn interacting facor f3 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 / Neutral Protease Domain 2 / Neutral Protease; domain 2 / Peptidase M4/M1, CTD superfamily / Neutral zinc metallopeptidases, zinc-binding region signature. / Alpha Horseshoe / Immunoglobulin-like / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-7O2 / BROMIDE ION / Leucyl-cystinyl aminopeptidase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.53 Å
AuthorsMpakali, A. / Stratikos, E. / Saridakis, E. / Giastas, P.
Funding support United Kingdom, Greece, United States, 3items
OrganizationGrant numberCountry
European Community's Seventh Framework Programme (FP7/2007-2013)BioStruct-X (grant agreement No 283570) United Kingdom
Education and Lifelong Learning? of the National Strategic Reference Framework: Research Funding Program of the General Secretariat for Research & Technologygrant no. ERC-14 to ES Greece
Harry J. Lloyd Charitable trust United States
CitationJournal: J. Med. Chem. / Year: 2017
Title: Ligand-Induced Conformational Change of Insulin-Regulated Aminopeptidase: Insights on Catalytic Mechanism and Active Site Plasticity.
Authors: Mpakali, A. / Saridakis, E. / Harlos, K. / Zhao, Y. / Kokkala, P. / Georgiadis, D. / Giastas, P. / Papakyriakou, A. / Stratikos, E.
History
DepositionNov 30, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 5, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2017Group: Database references
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_conn_angle / pdbx_validate_close_contact / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Leucyl-cystinyl aminopeptidase
B: Leucyl-cystinyl aminopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)217,24555
Polymers202,3642
Non-polymers14,88153
Water4,324240
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A: Leucyl-cystinyl aminopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,95632
Polymers101,1821
Non-polymers8,77431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Leucyl-cystinyl aminopeptidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,28923
Polymers101,1821
Non-polymers6,10722
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)112.240, 143.170, 148.990
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Leucyl-cystinyl aminopeptidase / Cystinyl aminopeptidase / Insulin-regulated membrane aminopeptidase / Insulin-responsive ...Cystinyl aminopeptidase / Insulin-regulated membrane aminopeptidase / Insulin-responsive aminopeptidase / IRAP / Oxytocinase / OTase / Placental leucine aminopeptidase / P-LAP


Mass: 101182.039 Da / Num. of mol.: 2 / Fragment: UNP residues 155-1025
Source method: isolated from a genetically manipulated source
Details: R is from the cloning, TETSQVAPA is the Rho1D4 tag / Source: (gene. exp.) Homo sapiens (human) / Gene: LNPEP, OTASE / Details (production host): TETSQVAPA is the Rho1D4 tag / Cell (production host): transformed with adenovirus 5 DNA / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / Tissue (production host): embryonic kidney / References: UniProt: Q9UIQ6, cystinyl aminopeptidase

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Sugars , 5 types, 28 molecules

#2: 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: obtained synthetically
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#3: 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.: 5 / Source method: obtained synthetically
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-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.: 7 / Source method: obtained synthetically
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}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: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#6: 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.: 12 / 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 , 4 types, 265 molecules

#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: Zn
#8: Chemical ChemComp-7O2 / [(2~{S})-2-[[(2~{S})-1-azanyl-1-oxidanylidene-3-phenyl-propan-2-yl]carbamoyl]-4,4-diphenyl-butyl]-[(1~{R})-1-azanyl-3-phenyl-propyl]phosphinic acid


Mass: 597.684 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C35H40N3O4P
#9: Chemical...
ChemComp-BR / BROMIDE ION


Mass: 79.904 Da / Num. of mol.: 21 / Source method: obtained synthetically / Formula: Br
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 240 / Source method: isolated from a natural source / Formula: H2O

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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: 2.39 Å3/Da / Density % sol: 58.98 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 18.8% (w/v) PEG of mean MW 20000, 37.6% (v/v) PEG monomethyl ether of mean MW 500, 50.2 mM Bicine, 43.8 mM Trizma base (pH of buffer mixture: 8.5) and 0.282 M each of the following halogens: ...Details: 18.8% (w/v) PEG of mean MW 20000, 37.6% (v/v) PEG monomethyl ether of mean MW 500, 50.2 mM Bicine, 43.8 mM Trizma base (pH of buffer mixture: 8.5) and 0.282 M each of the following halogens: Sodium fluoride, Sodium bromide and Sodium iodide

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 6, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.53→40.805 Å / Num. obs: 80735 / % possible obs: 100 % / Redundancy: 13.2 % / Biso Wilson estimate: 45.968 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.199 / Net I/σ(I): 0.812
Reflection shellResolution: 2.53→2.6 Å / Redundancy: 13.1 % / Mean I/σ(I) obs: 1.6 / CC1/2: 0.451 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2YD0

2yd0


Resolution: 2.53→40.805 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.54 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2292 3983 4.94 %
Rwork0.1738 --
obs0.1766 80655 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.53→40.805 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14085 0 890 240 15215
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0115557
X-RAY DIFFRACTIONf_angle_d1.37821220
X-RAY DIFFRACTIONf_dihedral_angle_d15.6195690
X-RAY DIFFRACTIONf_chiral_restr0.0732507
X-RAY DIFFRACTIONf_plane_restr0.0062587
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.53-2.56090.31711360.27122747X-RAY DIFFRACTION100
2.5609-2.59330.32851340.26952678X-RAY DIFFRACTION100
2.5933-2.62740.34971340.25512708X-RAY DIFFRACTION100
2.6274-2.66340.32251410.26472720X-RAY DIFFRACTION100
2.6634-2.70140.30151410.23672689X-RAY DIFFRACTION100
2.7014-2.74170.33191400.24012721X-RAY DIFFRACTION100
2.7417-2.78460.30561270.24892689X-RAY DIFFRACTION100
2.7846-2.83020.29781570.23032715X-RAY DIFFRACTION100
2.8302-2.8790.3111510.222717X-RAY DIFFRACTION100
2.879-2.93130.26921570.21922690X-RAY DIFFRACTION100
2.9313-2.98770.26831570.22432695X-RAY DIFFRACTION100
2.9877-3.04870.28351550.21522714X-RAY DIFFRACTION100
3.0487-3.11490.27981190.19332733X-RAY DIFFRACTION100
3.1149-3.18740.25351290.19492725X-RAY DIFFRACTION100
3.1874-3.2670.27241470.1872706X-RAY DIFFRACTION100
3.267-3.35530.25431470.19352734X-RAY DIFFRACTION100
3.3553-3.4540.23791490.18222736X-RAY DIFFRACTION100
3.454-3.56540.28011350.18012725X-RAY DIFFRACTION100
3.5654-3.69280.24791310.17252735X-RAY DIFFRACTION100
3.6928-3.84050.2121360.15982755X-RAY DIFFRACTION100
3.8405-4.01520.18981370.15422751X-RAY DIFFRACTION100
4.0152-4.22670.19211600.14122731X-RAY DIFFRACTION100
4.2267-4.49120.19571530.13452753X-RAY DIFFRACTION100
4.4912-4.83740.16991380.1242740X-RAY DIFFRACTION100
4.8374-5.32330.1911240.13682825X-RAY DIFFRACTION100
5.3233-6.09140.21191370.15882776X-RAY DIFFRACTION100
6.0914-7.66620.2141570.17082824X-RAY DIFFRACTION100
7.6662-40.81020.17351540.15572940X-RAY DIFFRACTION100

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