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- PDB-6y0f: Structure of human FAPalpha in complex with linagliptin -

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Basic information

Entry
Database: PDB / ID: 6y0f
TitleStructure of human FAPalpha in complex with linagliptin
ComponentsProlyl endopeptidase FAP
KeywordsHYDROLASE / FAP inhibitor complex DPP4 linagliptin
Function / homology
Function and homology information


negative regulation of extracellular matrix organization / melanocyte proliferation / peptidase complex / melanocyte apoptotic process / regulation of collagen catabolic process / negative regulation of cell proliferation involved in contact inhibition / prolyl oligopeptidase / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / basal part of cell ...negative regulation of extracellular matrix organization / melanocyte proliferation / peptidase complex / melanocyte apoptotic process / regulation of collagen catabolic process / negative regulation of cell proliferation involved in contact inhibition / prolyl oligopeptidase / negative regulation of extracellular matrix disassembly / dipeptidyl-peptidase IV / basal part of cell / regulation of fibrinolysis / dipeptidyl-peptidase activity / positive regulation of execution phase of apoptosis / lamellipodium membrane / Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases / endothelial cell migration / serine-type peptidase activity / proteolysis involved in protein catabolic process / ruffle membrane / integrin binding / apical part of cell / lamellipodium / peptidase activity / angiogenesis / endopeptidase activity / protease binding / regulation of cell cycle / cell adhesion / serine-type endopeptidase activity / focal adhesion / cell surface / protein homodimerization activity / proteolysis / extracellular space / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Peptidase S9, serine active site / Dipeptidylpeptidase IV, N-terminal domain / Dipeptidyl peptidase IV (DPP IV) N-terminal region / Peptidase S9, prolyl oligopeptidase, catalytic domain / Prolyl oligopeptidase family / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Chem-356 / Prolyl endopeptidase FAP
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.924 Å
AuthorsNar, H. / Schnapp, G. / Schreiner, P.
CitationJournal: To Be Published
Title: Structure of human FAPalpha in complex with linagliptin
Authors: Nar, H. / Schnapp, G. / Schreiner, P.
History
DepositionFeb 7, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 17, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Prolyl endopeptidase FAP
B: Prolyl endopeptidase FAP
C: Prolyl endopeptidase FAP
D: Prolyl endopeptidase FAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)341,54523
Polymers334,5174
Non-polymers7,02819
Water0
1
A: Prolyl endopeptidase FAP
B: Prolyl endopeptidase FAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,94812
Polymers167,2582
Non-polymers3,69010
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8830 Å2
ΔGint21 kcal/mol
Surface area59890 Å2
MethodPISA
2
C: Prolyl endopeptidase FAP
D: Prolyl endopeptidase FAP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,59711
Polymers167,2582
Non-polymers3,3389
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8520 Å2
ΔGint19 kcal/mol
Surface area60300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.586, 253.604, 115.247
Angle α, β, γ (deg.)90.000, 89.760, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Non-polymers , 2 types, 8 molecules ABCD

#1: Protein
Prolyl endopeptidase FAP / 170 kDa melanoma membrane-bound gelatinase / Dipeptidyl peptidase FAP / Fibroblast activation ...170 kDa melanoma membrane-bound gelatinase / Dipeptidyl peptidase FAP / Fibroblast activation protein alpha / FAPalpha / Gelatine degradation protease FAP / Integral membrane serine protease / Post-proline cleaving enzyme / Serine integral membrane protease / SIMP / Surface-expressed protease / Seprase


Mass: 83629.148 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FAP
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q12884, prolyl oligopeptidase, dipeptidyl-peptidase IV, Hydrolases; Acting on peptide bonds (peptidases); Serine endopeptidases
#6: Chemical
ChemComp-356 / 8-[(3R)-3-Aminopiperidin-1-yl]-7-but-2-yn-1-yl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-d ione / Linagliptin / Linagliptin


Mass: 472.542 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H28N8O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM

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Sugars , 4 types, 15 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.: 5
Source method: isolated from a genetically manipulated source
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
#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.: 1
Source method: isolated from a genetically manipulated source
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 alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 367.349 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
LFucpa1-6DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2/a6-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(6+1)][a-L-Fucp]{}}}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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
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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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: 2.95 Å3/Da / Density % sol: 58.34 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 9 / Details: 35% (v/v) PEG2000MME, 0.40 M lithium salt

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 1, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.92→48 Å / Num. obs: 81742 / % possible obs: 98 % / Redundancy: 2.9 % / Rsym value: 0.098 / Net I/σ(I): 11.8
Reflection shellResolution: 2.92→3.15 Å / Num. unique obs: 16579 / Rsym value: 0.447

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Processing

Software
NameVersionClassification
XDSdata reduction
BUSTER2.11.7 (17-DEC-2019)refinement
PDB_EXTRACT3.25data extraction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1z68

1z68


Resolution: 2.924→47.93 Å / Cor.coef. Fo:Fc: 0.868 / Cor.coef. Fo:Fc free: 0.824 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.368
RfactorNum. reflection% reflectionSelection details
Rfree0.243 656 0.8 %RANDOM
Rwork0.2075 ---
obs0.2078 81742 98 %-
Displacement parametersBiso max: 107.12 Å2 / Biso mean: 52.73 Å2 / Biso min: 25.03 Å2
Baniso -1Baniso -2Baniso -3
1--5.214 Å20 Å2-2.916 Å2
2---13.4437 Å20 Å2
3---18.6577 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: final / Resolution: 2.924→47.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms23602 0 475 0 24077
Biso mean--65.47 --
Num. residues----2882
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d8378SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes4140HARMONIC5
X-RAY DIFFRACTIONt_it24837HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion3202SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact17033SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d24837HARMONIC20.007
X-RAY DIFFRACTIONt_angle_deg33851HARMONIC20.85
X-RAY DIFFRACTIONt_omega_torsion2.68
X-RAY DIFFRACTIONt_other_torsion17.05
LS refinement shellResolution: 2.924→2.96 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2656 18 0.7 %
Rwork0.2809 2537 -
obs--97.75 %
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)
10.55350.10050.1321.0355-0.22182.8599-0.0562-0.17820.01870.1220.0137-0.0134-0.0588-0.00860.0425-0.10160.05520.0161-0.1831-0.0254-0.156240.7084-69.310193.8115
20.73020.1706-0.01531.2438-0.08162.3490.0180.08910.0909-0.13480.05090.0253-0.0937-0.1391-0.0689-0.1160.02810.0272-0.1875-0.022-0.144432.3522-57.373938.5426
30.67340.0739-0.11520.94290.16422.6124-0.0353-0.1299-0.01230.14230.01750.02620.02810.00280.0178-0.06850.03560.0519-0.1838-0.0124-0.1781-6.033911.8672111.7051
40.76180.0882-0.20211.45860.4092.2413-0.03590.1216-0.1147-0.19850.0299-0.0398-0.01790.0670.006-0.1294-0.00990.0529-0.18760.0057-0.14041.6386-0.005956.3318
50.0137-0.4992-0.05810.4988-0.00580.0644-0.0151-0.04880.0061-0.1151-0.0615-0.00570.0264-0.03190.07660.0309-0.07150.06320.0928-0.0931-0.00417.2365-28.664574.214
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A37 - 757
2X-RAY DIFFRACTION2{ B|* }B39 - 757
3X-RAY DIFFRACTION3{ C|* }C36 - 757
4X-RAY DIFFRACTION4{ D|* }D38 - 757
5X-RAY DIFFRACTION5{ X|* }X1 - 4

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