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- PDB-3gmd: Structure-based design of 7-Azaindole-pyrrolidines as inhibitors ... -

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Basic information

Entry
Database: PDB / ID: 3gmd
TitleStructure-based design of 7-Azaindole-pyrrolidines as inhibitors of 11beta-Hydroxysteroid-Dehydrogenase type I
ComponentsCorticosteroid 11-beta-dehydrogenase isozyme 1
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / ALPHA/BETA / Endoplasmic reticulum / Glycoprotein / Lipid metabolism / Membrane / NADP / Oxidoreductase / Signal-anchor / Steroid metabolism / Transmembrane / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR COMPLEX
Function / homology
Function and homology information


mineralocorticoid metabolic process / Glucocorticoid biosynthesis / glucocorticoid catabolic process / regulation of pentose-phosphate shunt / glucocorticoid biosynthetic process / 11beta-hydroxysteroid dehydrogenase / 11-beta-hydroxysteroid dehydrogenase (NADP+) activity / cortisol dehydrogenase activity / 7beta-hydroxysteroid dehydrogenase (NADP+) / 7-beta-hydroxysteroid dehydrogenase (NADP+) activity ...mineralocorticoid metabolic process / Glucocorticoid biosynthesis / glucocorticoid catabolic process / regulation of pentose-phosphate shunt / glucocorticoid biosynthetic process / 11beta-hydroxysteroid dehydrogenase / 11-beta-hydroxysteroid dehydrogenase (NADP+) activity / cortisol dehydrogenase activity / 7beta-hydroxysteroid dehydrogenase (NADP+) / 7-beta-hydroxysteroid dehydrogenase (NADP+) activity / Prednisone ADME / steroid catabolic process / steroid binding / lung development / apical part of cell / NADP binding / nuclear membrane / intracellular membrane-bounded organelle / endoplasmic reticulum membrane / protein homodimerization activity
Similarity search - Function
short chain dehydrogenase / Short-chain dehydrogenase/reductase, conserved site / Short-chain dehydrogenases/reductases family signature. / Short-chain dehydrogenase/reductase SDR / NAD(P)-binding Rossmann-like Domain / NAD(P)-binding domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-2M3 / Chem-NDP / 11-beta-hydroxysteroid dehydrogenase 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.28 Å
AuthorsValeur, E. / Lepifre, F. / Roche, D. / Christmann-Franck, S. / Hillertz, P. / Musil, D.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11 beta-hydroxysteroid dehydrogenase type I.
Authors: Valeur, E. / Christmann-Franck, S. / Lepifre, F. / Carniato, D. / Cravo, D. / Charon, C. / Bozec, S. / Musil, D. / Hillertz, P. / Doare, L. / Schmidlin, F. / Lecomte, M. / Schultz, M. / Roche, D.
History
DepositionMar 13, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 17, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 4, 2013Group: Database references
Revision 1.3Nov 1, 2017Group: Advisory / Refinement description
Category: pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / software
Revision 1.4Feb 21, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
C: Corticosteroid 11-beta-dehydrogenase isozyme 1
D: Corticosteroid 11-beta-dehydrogenase isozyme 1
E: Corticosteroid 11-beta-dehydrogenase isozyme 1
F: Corticosteroid 11-beta-dehydrogenase isozyme 1
G: Corticosteroid 11-beta-dehydrogenase isozyme 1
H: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)241,47933
Polymers231,8808
Non-polymers9,59925
Water9,494527
1
A: Corticosteroid 11-beta-dehydrogenase isozyme 1
B: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,2507
Polymers57,9702
Non-polymers2,2805
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5390 Å2
ΔGint-66 kcal/mol
Surface area23140 Å2
MethodPISA
2
C: Corticosteroid 11-beta-dehydrogenase isozyme 1
D: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,4429
Polymers57,9702
Non-polymers2,4727
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5900 Å2
ΔGint-97 kcal/mol
Surface area23070 Å2
MethodPISA
3
E: Corticosteroid 11-beta-dehydrogenase isozyme 1
F: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,3468
Polymers57,9702
Non-polymers2,3766
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5880 Å2
ΔGint-100 kcal/mol
Surface area23250 Å2
MethodPISA
4
G: Corticosteroid 11-beta-dehydrogenase isozyme 1
H: Corticosteroid 11-beta-dehydrogenase isozyme 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,4429
Polymers57,9702
Non-polymers2,4727
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6020 Å2
ΔGint-99 kcal/mol
Surface area23310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)127.336, 70.486, 132.956
Angle α, β, γ (deg.)90.00, 91.78, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Corticosteroid 11-beta-dehydrogenase isozyme 1 / 11-beta-hydroxysteroid dehydrogenase 1 / 11-beta-HSD1 / 11-DH / 11beta-HSD1A


Mass: 28984.939 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Description: Humanized mouse 11-beta HSD / Gene: Hsd11, Hsd11b1, HSD11L / Production host: Escherichia coli (E. coli)
References: UniProt: P50172, 11beta-hydroxysteroid dehydrogenase
#2: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical
ChemComp-2M3 / 2-methyl-3-{(3S)-1-[(1-pyridin-2-ylcyclopropyl)carbonyl]pyrrolidin-3-yl}-1H-pyrrolo[2,3-b]pyridine


Mass: 346.426 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H22N4O
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 527 / 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: 2.57 Å3/Da / Density % sol: 52.18 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.28→132.45 Å / Num. all: 107370 / Num. obs: 103009 / % possible obs: 95.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.8 % / Rmerge(I) obs: 0.088 / Net I/σ(I): 9.27
Reflection shellResolution: 2.28→2.34 Å / Redundancy: 2.45 % / Rmerge(I) obs: 0.354 / Mean I/σ(I) obs: 9.3 / Num. unique all: 7573 / % possible all: 96.2

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Processing

Software
NameClassification
AMoREphasing
CNXrefinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.28→70 Å / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.306 1260 -random
Rwork0.252 ---
all0.27 107370 --
obs0.254 103009 95.4 %-
Refinement stepCycle: LAST / Resolution: 2.28→70 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16200 0 637 527 17364

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