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- PDB-5sy3: Structure-based design of a new series of N-piperidin-3-ylpyrimid... -

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Basic information

Entry
Database: PDB / ID: 5sy3
TitleStructure-based design of a new series of N-piperidin-3-ylpyrimidine-5-carboxamides as renin inhibitors
ComponentsRenin
KeywordsHYDROLASE/HYDROLASE INHIBITOR / protein-ligand complex / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


renin / juxtaglomerular apparatus development / mesonephros development / response to cGMP / renin-angiotensin regulation of aldosterone production / drinking behavior / regulation of MAPK cascade / response to immobilization stress / angiotensin maturation / Metabolism of Angiotensinogen to Angiotensins ...renin / juxtaglomerular apparatus development / mesonephros development / response to cGMP / renin-angiotensin regulation of aldosterone production / drinking behavior / regulation of MAPK cascade / response to immobilization stress / angiotensin maturation / Metabolism of Angiotensinogen to Angiotensins / amyloid-beta metabolic process / cell maturation / response to cAMP / insulin-like growth factor receptor binding / hormone-mediated signaling pathway / kidney development / regulation of blood pressure / male gonad development / cellular response to xenobiotic stimulus / apical part of cell / peptidase activity / response to lipopolysaccharide / aspartic-type endopeptidase activity / signaling receptor binding / proteolysis / extracellular space / extracellular region / plasma membrane
Similarity search - Function
Renin-like domain / Aspartic peptidase, N-terminal / A1 Propeptide / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site ...Renin-like domain / Aspartic peptidase, N-terminal / A1 Propeptide / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-74Z / DI(HYDROXYETHYL)ETHER / Renin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsSnell, G.P. / Behnke, C.A. / Okada, K. / Hideyuki, O. / Sang, B.C. / Lane, W.
CitationJournal: Bioorg.Med.Chem. / Year: 2016
Title: Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors.
Authors: Imaeda, Y. / Tawada, M. / Suzuki, S. / Tomimoto, M. / Kondo, M. / Tarui, N. / Sanada, T. / Kanagawa, R. / Snell, G. / Behnke, C.A. / Kubo, K. / Kuroita, T.
History
DepositionAug 10, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 2, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 9, 2016Group: Database references
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / citation / 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_oper_list / 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.occupancy / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _citation.journal_id_CSD / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Renin
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,86521
Polymers74,3082
Non-polymers2,55719
Water6,828379
1
A: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,47411
Polymers37,1541
Non-polymers1,32010
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,39110
Polymers37,1541
Non-polymers1,2389
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: Renin
hetero molecules

A: Renin
hetero molecules

A: Renin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)115,42133
Polymers111,4623
Non-polymers3,95930
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area10110 Å2
ΔGint15 kcal/mol
Surface area39120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)139.192, 139.192, 139.192
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number198
Space group name H-MP213

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Renin / / Angiotensinogenase


Mass: 37153.852 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: REN / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P00797, renin

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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-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: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
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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Non-polymers , 5 types, 396 molecules

#4: Chemical ChemComp-74Z / N-[(furan-2-yl)methyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine


Mass: 285.364 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H15N3OS
#5: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#7: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400 / Polyethylene glycol


Mass: 238.278 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 379 / 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: 3.02 Å3/Da / Density % sol: 59.33 % / Mosaicity: 0.819 °
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.9 / Details: 23% PEG600, 0.06M citrate, 0.04M citric acid

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Jan 21, 2006
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→50.01 Å / Num. obs: 40166 / % possible obs: 99.9 % / Redundancy: 4.3 % / Rmerge(I) obs: 0.07 / Net I/av σ(I): 19.359 / Net I/σ(I): 11.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.3-2.384.20.5061100
2.38-2.484.20.4151100
2.48-2.594.30.3291100
2.59-2.734.30.2311100
2.73-2.94.30.1641100
2.9-3.124.40.1111100
3.12-3.444.40.0761100
3.44-3.934.30.056199.9
3.93-4.954.30.042199.9
4.95-504.20.032199.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
MOLREPphasing
REFMAC5.8.0135refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→50.01 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.928 / SU B: 11.79 / SU ML: 0.149 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.273 / ESU R Free: 0.214 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2367 1998 5 %RANDOM
Rwork0.1921 ---
obs0.1943 37946 99.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 89.7 Å2 / Biso mean: 42.034 Å2 / Biso min: 18.01 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 2.3→50.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5097 0 156 379 5632
Biso mean--56.59 47.62 -
Num. residues----668
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0195376
X-RAY DIFFRACTIONr_bond_other_d0.0020.024964
X-RAY DIFFRACTIONr_angle_refined_deg1.2771.9727269
X-RAY DIFFRACTIONr_angle_other_deg0.854311426
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0865663
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.18324.085213
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.97115823
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.5721518
X-RAY DIFFRACTIONr_chiral_restr0.070.2829
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025956
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021208
X-RAY DIFFRACTIONr_mcbond_it1.1472.7982667
X-RAY DIFFRACTIONr_mcbond_other1.1392.7982666
X-RAY DIFFRACTIONr_mcangle_it1.8844.1883325
LS refinement shellResolution: 2.299→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.264 143 -
Rwork0.226 2813 -
all-2956 -
obs--99.86 %
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)
11.6075-0.93630.23671.8626-0.52311.9726-0.00370.0520.1822-0.0327-0.0216-0.1916-0.11180.18480.02530.0561-0.02290.04130.0218-0.00580.0568-21.683217.6534-0.2122
21.24931.29860.10263.1020.51460.8156-0.11190.11250.1545-0.19050.13020.0393-0.1965-0.0049-0.01840.05810.0067-0.00770.050.01390.0275-38.6248-5.8666-23.4313
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 78
2X-RAY DIFFRACTION1A79 - 91
3X-RAY DIFFRACTION1A92 - 154
4X-RAY DIFFRACTION1A155 - 248
5X-RAY DIFFRACTION1A249 - 265
6X-RAY DIFFRACTION1A266 - 280
7X-RAY DIFFRACTION1A281 - 298
8X-RAY DIFFRACTION1A299 - 302
9X-RAY DIFFRACTION1A303 - 312
10X-RAY DIFFRACTION1A313 - 340
11X-RAY DIFFRACTION2B2 - 78
12X-RAY DIFFRACTION2B79 - 91
13X-RAY DIFFRACTION2B92 - 154
14X-RAY DIFFRACTION2B155 - 248
15X-RAY DIFFRACTION2B249 - 265
16X-RAY DIFFRACTION2B266 - 280
17X-RAY DIFFRACTION2B281 - 298
18X-RAY DIFFRACTION2B299 - 302
19X-RAY DIFFRACTION2B303 - 312
20X-RAY DIFFRACTION2B313 - 340

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