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- PDB-5iv4: Crystal structure of the human soluble adenylyl cyclase in comple... -

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Basic information

Entry
Database: PDB / ID: 5iv4
TitleCrystal structure of the human soluble adenylyl cyclase in complex with the allosteric inhibitor LRE1
ComponentsAdenylate cyclase type 10
KeywordsLYASE / human soluble Adenylyl Cyclase complex LRE1 inhibitor
Function / homology
Function and homology information


negative regulation of cardiac muscle cell contraction / astrocyte end-foot / mitochondrial ATP transmembrane transport / bicarbonate binding / epithelial cilium movement involved in extracellular fluid movement / neuron projection retraction / positive regulation of glycogen catabolic process / : / central region of growth cone / regulation of mitophagy ...negative regulation of cardiac muscle cell contraction / astrocyte end-foot / mitochondrial ATP transmembrane transport / bicarbonate binding / epithelial cilium movement involved in extracellular fluid movement / neuron projection retraction / positive regulation of glycogen catabolic process / : / central region of growth cone / regulation of mitophagy / glucose catabolic process / regulation of membrane repolarization / adenylate cyclase / basal part of cell / positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / cAMP biosynthetic process / positive regulation of ossification / adenylate cyclase activity / positive regulation of protein targeting to mitochondrion / positive regulation of reactive oxygen species biosynthetic process / neuron projection extension / positive regulation of vascular associated smooth muscle cell apoptotic process / positive regulation of mitochondrial depolarization / positive regulation of ATP biosynthetic process / positive regulation of cardiac muscle hypertrophy / positive regulation of cardiac muscle cell apoptotic process / negative regulation of mitochondrial membrane potential / spermatid development / positive regulation of axon extension / Hedgehog 'off' state / negative regulation of reactive oxygen species biosynthetic process / neuron projection maintenance / positive regulation of peptidyl-threonine phosphorylation / cilium / manganese ion binding / ATPase binding / cytoskeleton / intracellular signal transduction / apical plasma membrane / neuronal cell body / dendrite / perinuclear region of cytoplasm / magnesium ion binding / mitochondrion / extracellular region / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Adenylate cyclase, type 10 / Nucleotide cyclase, GGDEF domain / Adenylyl cyclase class-3/4/guanylyl cyclase / Adenylate and Guanylate cyclase catalytic domain / Guanylate cyclase domain profile. / Nucleotide cyclase / Alpha-Beta Plaits / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
ACETATE ION / Chem-LRI / DI(HYDROXYETHYL)ETHER / Adenylate cyclase type 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.79 Å
AuthorsKleinboelting, S. / Steegborn, C.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationSTE1701/11 Germany
CitationJournal: Nat.Chem.Biol. / Year: 2016
Title: Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.
Authors: Ramos-Espiritu, L. / Kleinboelting, S. / Navarrete, F.A. / Alvau, A. / Visconti, P.E. / Valsecchi, F. / Starkov, A. / Manfredi, G. / Buck, H. / Adura, C. / Zippin, J.H. / van den Heuvel, J. ...Authors: Ramos-Espiritu, L. / Kleinboelting, S. / Navarrete, F.A. / Alvau, A. / Visconti, P.E. / Valsecchi, F. / Starkov, A. / Manfredi, G. / Buck, H. / Adura, C. / Zippin, J.H. / van den Heuvel, J. / Glickman, J.F. / Steegborn, C. / Levin, L.R. / Buck, J.
History
DepositionMar 18, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 17, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2016Group: Database references
Revision 1.2Sep 28, 2016Group: Database references
Revision 1.3Nov 30, 2022Group: Author supporting evidence / Database references ...Author supporting evidence / Database references / Source and taxonomy / Structure summary
Category: database_2 / entity_src_gen ...database_2 / entity_src_gen / pdbx_audit_support / struct
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.gene_src_common_name / _pdbx_audit_support.funding_organization / _struct.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Adenylate cyclase type 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,52516
Polymers54,2701
Non-polymers1,25515
Water6,449358
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3100 Å2
ΔGint13 kcal/mol
Surface area19940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.298, 99.298, 99.386
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Adenylate cyclase type 10 / AH-related protein / Adenylate cyclase homolog / Germ cell soluble adenylyl cyclase / sAC / ...AH-related protein / Adenylate cyclase homolog / Germ cell soluble adenylyl cyclase / sAC / Testicular soluble adenylyl cyclase


Mass: 54269.664 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Cys255 modified by BME which is in the purification buffer
Source: (gene. exp.) Homo sapiens (human) / Gene: ADCY10, SAC / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96PN6, adenylate cyclase

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Non-polymers , 8 types, 373 molecules

#2: Chemical ChemComp-LRI / 6-chloro-N~4~-cyclopropyl-N~4~-[(thiophen-2-yl)methyl]pyrimidine-2,4-diamine


Mass: 280.776 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H13ClN4S
#3: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 358 / 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: 2.3 Å3/Da / Density % sol: 47 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 100 mM sodium acetate pH 4.8 200 mM tri-sodium-citrate 15% (w/v) PEG 4000 10% (v/v) glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.918007 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.918007 Å / Relative weight: 1
ReflectionResolution: 1.79→44.42 Å / Num. obs: 599809 / % possible obs: 99.9 % / Redundancy: 11.4 % / Rmerge(I) obs: 0.115 / Net I/σ(I): 16.3
Reflection shellResolution: 1.79→1.9 Å / Redundancy: 11.2 % / Rmerge(I) obs: 1.192 / Mean I/σ(I) obs: 2.07 / % possible all: 99.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
XDSdata reduction
Cootmodel building
MOLREPphasing
XSCALEdata scaling
RefinementResolution: 1.79→44.42 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.953 / SU B: 2.647 / SU ML: 0.08 / Cross valid method: THROUGHOUT / ESU R: 0.103 / ESU R Free: 0.109 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20626 2621 5 %RANDOM
Rwork0.15972 ---
obs0.162 49787 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.704 Å2
Baniso -1Baniso -2Baniso -3
1-0.27 Å20.13 Å20 Å2
2--0.27 Å20 Å2
3----0.86 Å2
Refinement stepCycle: LAST / Resolution: 1.79→44.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3660 0 76 358 4094
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0193897
X-RAY DIFFRACTIONr_bond_other_d0.0020.023750
X-RAY DIFFRACTIONr_angle_refined_deg2.0791.9675274
X-RAY DIFFRACTIONr_angle_other_deg1.1333.0018622
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4365485
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.72924.624173
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.4915670
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.3561513
X-RAY DIFFRACTIONr_chiral_restr0.1590.2588
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0214352
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02892
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.2412.7341872
X-RAY DIFFRACTIONr_mcbond_other3.2122.7311869
X-RAY DIFFRACTIONr_mcangle_it4.3394.0732341
X-RAY DIFFRACTIONr_mcangle_other4.3394.0752342
X-RAY DIFFRACTIONr_scbond_it4.4513.2422025
X-RAY DIFFRACTIONr_scbond_other4.4373.2412025
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.6444.6482917
X-RAY DIFFRACTIONr_long_range_B_refined8.82223.64597
X-RAY DIFFRACTIONr_long_range_B_other8.82123.6034598
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.789→1.835 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.325 192 -
Rwork0.296 3654 -
obs--99 %

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