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- PDB-1fbz: Structure-based design of a novel, osteoclast-selective, nonpepti... -

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Basic information

Entry
Database: PDB / ID: 1fbz
TitleStructure-based design of a novel, osteoclast-selective, nonpeptide Src SH2 inhibitor with in vivo anti-resorptive activity
ComponentsPROTO-ONCOGENE TYROSINE-PROTEIN KINASE LCK
KeywordsTRANSFERASE / SH2 DOMAIN / NONPEPTIDE INHIBITOR
Function / homology
Function and homology information


regulation of lymphocyte activation / positive regulation of leukocyte cell-cell adhesion / Fc-gamma receptor signaling pathway / CD28 co-stimulation / FLT3 signaling through SRC family kinases / intracellular zinc ion homeostasis / Nef and signal transduction / CD4 receptor binding / Nef Mediated CD4 Down-regulation / positive regulation of heterotypic cell-cell adhesion ...regulation of lymphocyte activation / positive regulation of leukocyte cell-cell adhesion / Fc-gamma receptor signaling pathway / CD28 co-stimulation / FLT3 signaling through SRC family kinases / intracellular zinc ion homeostasis / Nef and signal transduction / CD4 receptor binding / Nef Mediated CD4 Down-regulation / positive regulation of heterotypic cell-cell adhesion / Interleukin-2 signaling / CD28 dependent Vav1 pathway / Regulation of KIT signaling / leukocyte migration / CTLA4 inhibitory signaling / protein serine/threonine phosphatase activity / phospholipase activator activity / CD8 receptor binding / pericentriolar material / positive regulation of T cell receptor signaling pathway / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / PECAM1 interactions / CD28 dependent PI3K/Akt signaling / phospholipase binding / hemopoiesis / RHOH GTPase cycle / Generation of second messenger molecules / immunological synapse / T cell differentiation / PD-1 signaling / phosphatidylinositol 3-kinase binding / positive regulation of intrinsic apoptotic signaling pathway / T cell receptor binding / peptidyl-tyrosine autophosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / GPVI-mediated activation cascade / release of sequestered calcium ion into cytosol / T cell costimulation / phosphotyrosine residue binding / SH2 domain binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / non-specific protein-tyrosine kinase / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / Signaling by SCF-KIT / platelet activation / : / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of T cell activation / Downstream TCR signaling / PIP3 activates AKT signaling / DAP12 signaling / T cell receptor signaling pathway / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / protein phosphatase binding / intracellular signal transduction / response to xenobiotic stimulus / protein phosphorylation / membrane raft / innate immune response / signaling receptor binding / protein kinase binding / extracellular exosome / ATP binding / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Lck, SH3 domain / Tyrosine-protein kinase Lck, SH2 domain / SH2 domain / SHC Adaptor Protein / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain ...Lck, SH3 domain / Tyrosine-protein kinase Lck, SH2 domain / SH2 domain / SHC Adaptor Protein / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-CC1 / Tyrosine-protein kinase Lck
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.4 Å
AuthorsShakespeare, W. / Yang, M. / Bohacek, R. / Cerasoli, F. / Stebbis, K. / Sundaramoorthi, R. / Vu, C. / Pradeepan, S. / Metcalf, C. / Haraldson, C. ...Shakespeare, W. / Yang, M. / Bohacek, R. / Cerasoli, F. / Stebbis, K. / Sundaramoorthi, R. / Vu, C. / Pradeepan, S. / Metcalf, C. / Haraldson, C. / Merry, T. / Dalgarno, D. / Narula, S. / Hatada, M. / Lu, X. / Van Schravendijk, M.R. / Adams, S. / Violette, S. / Smith, J. / Guan, W. / Bartlett, C. / Herson, J. / Iuliucci, J. / Weigele, M. / Sawyer, T.
CitationJournal: Proc.Natl.Acad.Sci.Usa / Year: 2000
Title: Structure-based design of an osteoclast-selective, nonpeptide src homology 2 inhibitor with in vivo antiresorptive activity.
Authors: Shakespeare, W. / Yang, M. / Bohacek, R. / Cerasoli, F. / Stebbins, K. / Sundaramoorthi, R. / Azimioara, M. / Vu, C. / Pradeepan, S. / Metcalf, C. / Haraldson, C. / Merry, T. / Dalgarno, D. ...Authors: Shakespeare, W. / Yang, M. / Bohacek, R. / Cerasoli, F. / Stebbins, K. / Sundaramoorthi, R. / Azimioara, M. / Vu, C. / Pradeepan, S. / Metcalf, C. / Haraldson, C. / Merry, T. / Dalgarno, D. / Narula, S. / Hatada, M. / Lu, X. / van Schravendijk, M.R. / Adams, S. / Violette, S. / Smith, J. / Guan, W. / Bartlett, C. / Herson, J. / Iuliucci, J. / Weigele, M. / Sawyer, T.
History
DepositionJul 17, 2000Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 23, 2000Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 7, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE LCK
B: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE LCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1084
Polymers23,7772
Non-polymers1,3312
Water72140
1
A: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE LCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,5542
Polymers11,8881
Non-polymers6661
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE LCK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,5542
Polymers11,8881
Non-polymers6661
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)44.870, 56.260, 102.770
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein PROTO-ONCOGENE TYROSINE-PROTEIN KINASE LCK


Mass: 11888.279 Da / Num. of mol.: 2 / Fragment: SH2 DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: P06239, EC: 2.7.1.112
#2: Chemical ChemComp-CC1 / {4-[2-ACETYLAMINO-2-(3-CARBAMOYL-2-CYCLOHEXYLMETHOXY-6,7,8,9-TETRAHYDRO-5H-BENZOCYCLOHEPTEN-5YLCARBAMOYL)-ETHYL]-2-PHOSPHONO-PHENYL}-PHOSPHONIC ACID


Mass: 665.608 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H41N3O10P2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 40 / 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: 2.73 Å3/Da / Density % sol: 54.91 %
Crystal grow
*PLUS
Method: unknown
Components of the solutions
*PLUS
IDCommon nameCrystal-IDSol-ID
1PEG400011
2Tris11

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Data collection

DiffractionMean temperature: 113 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS II / Detector: IMAGE PLATE / Date: Oct 29, 1998
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→15 Å / Num. obs: 9476 / % possible obs: 88.3 % / Observed criterion σ(I): 2 / Redundancy: 6 % / Rmerge(I) obs: 0.09

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Processing

Software
NameClassification
DENZOdata reduction
SCALEPACKdata scaling
X-PLORmodel building
X-PLORrefinement
X-PLORphasing
RefinementResolution: 2.4→15 Å / σ(F): 2
RfactorNum. reflection% reflection
Rfree0.36 -10 %
Rwork0.23 --
obs0.23 9476 88.3 %
Refinement stepCycle: LAST / Resolution: 2.4→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2076 0 90 120 2286

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