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- PDB-8cnh: Crystal structure of human soluble adenylyl cyclase (sAC) in comp... -

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Basic information

Entry
Database: PDB / ID: 8cnh
TitleCrystal structure of human soluble adenylyl cyclase (sAC) in complex with inhibitor TDI-10512
ComponentsAdenylate cyclase type 10
KeywordsSIGNALING PROTEIN / cAMP / adenylyl cyclase / inhibitor / catalytic domain
Function / homology
Function and homology information


negative regulation of cardiac muscle cell contraction / mitochondrial ATP transmembrane transport / bicarbonate binding / epithelial cilium movement involved in extracellular fluid movement / neuron projection retraction / astrocyte end-foot / central region of growth cone / positive regulation of glycogen catabolic process / glucose catabolic process / regulation of mitophagy ...negative regulation of cardiac muscle cell contraction / mitochondrial ATP transmembrane transport / bicarbonate binding / epithelial cilium movement involved in extracellular fluid movement / neuron projection retraction / astrocyte end-foot / central region of growth cone / positive regulation of glycogen catabolic process / glucose catabolic process / regulation of mitophagy / 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 / neuron projection extension / positive regulation of vascular associated smooth muscle cell apoptotic process / positive regulation of ATP biosynthetic process / positive regulation of reactive oxygen species biosynthetic process / positive regulation of mitochondrial depolarization / positive regulation of cardiac muscle hypertrophy / spermatid development / negative regulation of mitochondrial membrane potential / positive regulation of axon extension / Hedgehog 'off' state / positive regulation of cardiac muscle cell apoptotic process / negative regulation of reactive oxygen species biosynthetic process / neuron projection maintenance / manganese ion binding / ATPase binding / cytoskeleton / intracellular signal transduction / cilium / 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 / Adenylate and Guanylate cyclase catalytic domain / Adenylyl cyclase class-3/4/guanylyl cyclase / Guanylate cyclase domain profile. / Nucleotide cyclase / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ACETATE ION / Chem-V6U / Adenylate cyclase type 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsSteegborn, C.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)STE1701/11 Germany
CitationJournal: J.Chem.Inf.Model. / Year: 2023
Title: Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation.
Authors: Sun, S. / Fushimi, M. / Rossetti, T. / Kaur, N. / Ferreira, J. / Miller, M. / Quast, J. / van den Heuvel, J. / Steegborn, C. / Levin, L.R. / Buck, J. / Myers, R.W. / Kargman, S. / Liverton, ...Authors: Sun, S. / Fushimi, M. / Rossetti, T. / Kaur, N. / Ferreira, J. / Miller, M. / Quast, J. / van den Heuvel, J. / Steegborn, C. / Levin, L.R. / Buck, J. / Myers, R.W. / Kargman, S. / Liverton, N. / Meinke, P.T. / Huggins, D.J.
History
DepositionFeb 23, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1May 17, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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: Adenylate cyclase type 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,63617
Polymers54,2701
Non-polymers1,36616
Water2,252125
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3360 Å2
ΔGint37 kcal/mol
Surface area19310 Å2
Unit cell
Length a, b, c (Å)99.140, 99.140, 99.601
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number173
Space group name H-MP63
Space group name HallP6c
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/2
#3: y,-x+y,z+1/2
#4: -y,x-y,z
#5: -x+y,-x,z
#6: -x,-y,z+1/2

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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: disulfid with mercaptoethanol at Cys255 / Source: (gene. exp.) Homo sapiens (human) / Gene: ADCY10, SAC / Production host: Escherichia coli (E. coli) / References: UniProt: Q96PN6, adenylate cyclase

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Non-polymers , 5 types, 141 molecules

#2: Chemical ChemComp-V6U / methyl 2-[[3-(2-azanyl-6-chloranyl-pyrimidin-4-yl)-1-methyl-pyrazol-4-yl]methyl]benzoate


Mass: 357.794 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H16ClN5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / Source method: isolated from a natural source / Formula: H2O

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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: 2.6 Å3/Da / Density % sol: 52.76 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 0.1 M sodium acetate pH 4.8, 0.2 M trisodium citrate, 15%(w/v) PEG 4000, 10%(v/v) glycerol
Temp details: 277

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 3, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2→44.38 Å / Num. obs: 36970 / % possible obs: 95.6 % / Redundancy: 10.4 % / Biso Wilson estimate: 37.83 Å2 / CC1/2: 0.994 / Rrim(I) all: 0.255 / Net I/σ(I): 6.7
Reflection shellResolution: 2→2.07 Å / Num. unique obs: 3263 / CC1/2: 0.1 / Rrim(I) all: 4.024 / % possible all: 64.5

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→44.38 Å / SU ML: 0.297 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 25.1786
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2367 1798 5 %
Rwork0.1888 34128 -
obs0.1911 35926 95.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 50.17 Å2
Refinement stepCycle: LAST / Resolution: 2→44.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3583 0 85 125 3793
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01843761
X-RAY DIFFRACTIONf_angle_d1.47385072
X-RAY DIFFRACTIONf_chiral_restr0.0785556
X-RAY DIFFRACTIONf_plane_restr0.0095644
X-RAY DIFFRACTIONf_dihedral_angle_d6.26093045
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.050.3572780.35421602X-RAY DIFFRACTION58.46
2.05-2.110.3441300.31722341X-RAY DIFFRACTION85.18
2.11-2.180.33341420.30362693X-RAY DIFFRACTION98.75
2.18-2.260.31321450.27492756X-RAY DIFFRACTION99.97
2.26-2.350.2851430.24532706X-RAY DIFFRACTION99.93
2.35-2.460.27891440.2272743X-RAY DIFFRACTION100
2.46-2.590.2621440.21512728X-RAY DIFFRACTION100
2.59-2.750.24161450.20062765X-RAY DIFFRACTION100
2.75-2.960.22961440.19962735X-RAY DIFFRACTION100
2.96-3.260.2431450.18552750X-RAY DIFFRACTION100
3.26-3.730.22721440.16132744X-RAY DIFFRACTION100
3.73-4.70.18641460.13672777X-RAY DIFFRACTION100
4.7-44.380.21981480.17452788X-RAY DIFFRACTION99.63
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)
12.39133967521-0.9411514616240.4142296041611.45857271884-0.1612278918621.444867089860.06592123582140.0579182644099-0.2423120204250.1099284166240.0002899721976720.03848537954060.112362737677-0.0057308295225-0.06281635196360.2558285804080.0114528257820.02044631333060.224978276853-0.001608095008650.246587405239-37.49742624511.85276348843.38981128076
21.50058331833-0.333001623673-0.02198174440642.3009513726-0.8897024029392.61291768693-0.0659113218386-0.220352621608-0.1447000414610.1297735708340.117893045144-0.009664683761760.4075809259680.0330718788131-0.04965601817770.3143620138750.034449174162-0.0244640658310.259920102650.01362574115390.286105658103-30.86287454226.6315761045211.5648160821
31.645767715810.43611008507-0.6183835896731.817653590421.262674797552.98822000071-0.02316697861630.309540784307-0.0803692511648-0.1496489429470.0381505016388-0.1919698729590.1057751057750.222938518665-0.001182007481850.3051713799850.06530774106810.04015015770820.28656181323-0.002495482079660.297382438587-27.61845329425.65555316342-13.6223110585
40.415079577531-0.503386728033-0.4149367971982.97035330822.138748957322.28620145484-0.1008366684140.207543013868-0.196148886259-0.178019208864-0.1808935381770.3367908627730.35375941046-0.1275670114590.2008597023080.4691246502670.008737423238950.0222699338140.390347476837-0.04912066488930.365903897048-35.2130323083-3.64059976859-18.2906248991
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 7 through 88 )
2X-RAY DIFFRACTION2chain 'A' and (resid 89 through 287 )
3X-RAY DIFFRACTION3chain 'A' and (resid 288 through 398 )
4X-RAY DIFFRACTION4chain 'A' and (resid 399 through 468 )

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