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- PDB-6umx: Structural basis for specific inhibition of extracellular activat... -

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Basic information

Entry
Database: PDB / ID: 6umx
TitleStructural basis for specific inhibition of extracellular activation of pro/latent myostatin by SRK-015
Components
  • GL29H4-16 Fab Heavy Chain,GL29H4-16 Fab Heavy Chain
  • GL29H4-16 Fab Light Chain,GL29H4-16 Fab Light Chain
  • Growth/differentiation factor 8
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / Myostatin / GDF8 / transforming growth factor beta / muscle wasting disease / antibody / fab / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


negative regulation of muscle hypertrophy / negative regulation of skeletal muscle tissue growth / negative regulation of myoblast proliferation / skeletal muscle satellite cell differentiation / myoblast migration involved in skeletal muscle regeneration / negative regulation of skeletal muscle satellite cell proliferation / negative regulation of satellite cell differentiation / skeletal muscle atrophy / ovulation cycle process / FOXO-mediated transcription of cell cycle genes ...negative regulation of muscle hypertrophy / negative regulation of skeletal muscle tissue growth / negative regulation of myoblast proliferation / skeletal muscle satellite cell differentiation / myoblast migration involved in skeletal muscle regeneration / negative regulation of skeletal muscle satellite cell proliferation / negative regulation of satellite cell differentiation / skeletal muscle atrophy / ovulation cycle process / FOXO-mediated transcription of cell cycle genes / response to gravity / negative regulation of myoblast differentiation / CD22 mediated BCR regulation / response to muscle activity / Fc epsilon receptor (FCERI) signaling / muscle organ development / Classical antibody-mediated complement activation / muscle cell cellular homeostasis / positive regulation of macrophage chemotaxis / Initial triggering of complement / response to testosterone / IgG immunoglobulin complex / immunoglobulin mediated immune response / FCGR activation / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Role of phospholipids in phagocytosis / Role of LAT2/NTAL/LAB on calcium mobilization / Scavenging of heme from plasma / positive regulation of lamellipodium assembly / response to electrical stimulus / negative regulation of insulin receptor signaling pathway / antigen binding / cellular response to dexamethasone stimulus / FCERI mediated Ca+2 mobilization / transforming growth factor beta receptor signaling pathway / FCGR3A-mediated IL10 synthesis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / cytokine activity / Regulation of Complement cascade / Cell surface interactions at the vascular wall / FCERI mediated MAPK activation / FCGR3A-mediated phagocytosis / growth factor activity / Regulation of actin dynamics for phagocytic cup formation / FCERI mediated NF-kB activation / response to estrogen / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / heparin binding / cellular response to hypoxia / response to ethanol / blood microparticle / Potential therapeutics for SARS / signaling receptor binding / positive regulation of DNA-templated transcription / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / membrane / identical protein binding / plasma membrane
Similarity search - Function
TGF-beta, propeptide / TGF-beta propeptide / Transforming growth factor beta, conserved site / TGF-beta family signature. / Transforming growth factor-beta-related / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Cystine-knot cytokine ...TGF-beta, propeptide / TGF-beta propeptide / Transforming growth factor beta, conserved site / TGF-beta family signature. / Transforming growth factor-beta-related / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Cystine-knot cytokine / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulin subtype / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Growth/differentiation factor 8 / Immunoglobulin lambda constant 2 / Anti-RhD monoclonal T125 gamma1 heavy chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.79 Å
AuthorsDagbay, K.B. / Treece, E. / Streich Jr., F.C. / Jackson, J.W. / Faucette, R.R. / Nikiforov, A. / Lin, S.C. / Bostion, C.J. / Nicholls, S.B. / Capili, A.D. / Carven, G.J.
CitationJournal: J.Biol.Chem. / Year: 2020
Title: Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015.
Authors: Dagbay, K.B. / Treece, E. / Streich Jr., F.C. / Jackson, J.W. / Faucette, R.R. / Nikiforov, A. / Lin, S.C. / Boston, C.J. / Nicholls, S.B. / Capili, A.D. / Carven, G.J.
History
DepositionOct 10, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 26, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Apr 29, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Growth/differentiation factor 8
L: GL29H4-16 Fab Light Chain,GL29H4-16 Fab Light Chain
H: GL29H4-16 Fab Heavy Chain,GL29H4-16 Fab Heavy Chain
l: GL29H4-16 Fab Light Chain,GL29H4-16 Fab Light Chain
h: GL29H4-16 Fab Heavy Chain,GL29H4-16 Fab Heavy Chain
B: Growth/differentiation factor 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)178,1407
Polymers178,0486
Non-polymers921
Water362
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area19400 Å2
ΔGint-127 kcal/mol
Surface area66270 Å2
Unit cell
Length a, b, c (Å)59.620, 110.010, 293.270
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12L
22l
13H
23h

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11CYSCYSSERSERAA42 - 37532 - 365
21CYSCYSSERSERBF42 - 37532 - 365
12VALVALPROPROLB3 - 2113 - 211
22VALVALPROPROlD3 - 2113 - 211
13ILEILEGLUGLUHC2 - 2252 - 225
23ILEILEGLUGLUhE2 - 2252 - 225

NCS ensembles :
ID
1
2
3

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Components

#1: Protein Growth/differentiation factor 8 / GDF-8 / Myostatin


Mass: 41642.332 Da / Num. of mol.: 2 / Fragment: UNP residues 24-375 / Mutation: D99A, R263A, R266A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MSTN, GDF8 / Plasmid: pTT5 / Cell line (production host): Expi293 HEK / Production host: Homo sapiens (human) / References: UniProt: O14793
#2: Antibody GL29H4-16 Fab Light Chain,GL29H4-16 Fab Light Chain


Mass: 22655.908 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pTT5 / Cell line (production host): Expi293 HEK / Production host: Homo sapiens (human) / References: UniProt: P0DOY2
#3: Antibody GL29H4-16 Fab Heavy Chain,GL29H4-16 Fab Heavy Chain


Mass: 24725.869 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pTT5 / Cell line (production host): Expi293 HEK / Production host: Homo sapiens (human) / References: UniProt: Q5EFE5
#4: 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
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.7 Å3/Da / Density % sol: 54.46 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.1 M sodium citrate, pH 5.5, 20% PEG3350, 15% 2-propanol, 3% trimethylamine N-oxide

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 22, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.79→146.63 Å / Num. obs: 49196 / % possible obs: 100 % / Redundancy: 5.1 % / Biso Wilson estimate: 79.718 Å2 / Rpim(I) all: 0.035 / Rrim(I) all: 0.079 / Net I/σ(I): 14.1
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all
2.79-2.845.31.21297624670.6451.487
7.56-40.434.640.91239126930.0140.032

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
xia2data scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entries 5GGU, 5F3H, 3HH2, 3RJR, & 5NTU

5ggu

5f3h

3hh2

3rjr

5ntu


Resolution: 2.79→40.43 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.927 / SU B: 39.776 / SU ML: 0.337 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.216 / ESU R Free: 0.364
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2643 2372 4.8 %RANDOM
Rwork0.217 ---
obs0.2193 46728 99.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 240.21 Å2 / Biso mean: 98.061 Å2 / Biso min: 30 Å2
Baniso -1Baniso -2Baniso -3
1--2.55 Å2-0 Å20 Å2
2--3.06 Å2-0 Å2
3----0.51 Å2
Refinement stepCycle: final / Resolution: 2.79→40.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10841 0 6 2 10849
Biso mean--85.07 65.18 -
Num. residues----1427
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0211252
X-RAY DIFFRACTIONr_bond_other_d0.0030.0210228
X-RAY DIFFRACTIONr_angle_refined_deg2.0721.95915318
X-RAY DIFFRACTIONr_angle_other_deg1.171323868
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.11151413
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.92824.188437
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.752151831
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.8071551
X-RAY DIFFRACTIONr_chiral_restr0.1280.21727
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.02112360
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022191
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A147700.15
12B147700.15
21L119040.12
22l119040.12
31H131860.1
32h131860.1
LS refinement shellResolution: 2.79→2.862 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.426 159 -
Rwork0.378 3430 -
all-3589 -
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)
11.1490.53830.16692.2290.17970.04120.0712-0.4014-0.02550.1622-0.13680.4250.0651-0.10710.06560.7238-0.13660.01970.8193-0.08730.36122.7111127.533166.4262
22.5534-0.72541.43480.3942-0.67171.6340.3186-0.1845-0.3838-0.178-0.00380.12470.5355-0.2442-0.31480.5722-0.1166-0.02360.1473-0.0110.262465.8822131.8448194.6182
31.9372-1.03110.95280.6042-0.4930.7845-0.12250.10920.2730.0571-0.1205-0.14180.0844-0.05570.2430.4961-0.05110.01660.1017-0.0480.271573.7283146.6147193.5366
42.34442.01421.28632.28271.52221.5673-0.7310.37170.848-0.49320.270.776-0.81650.21410.4610.7438-0.1641-0.20370.06860.15940.651467.511597.0039204.5725
52.03091.03651.76151.23881.04252.5157-0.15410.2331-0.03730.25180.13280.1413-0.08970.050.02120.32550.0040.09040.0539-0.0220.373669.042480.8658211.5079
60.3013-0.5790.4572.2299-0.53150.80090.14460.0462-0.0695-0.6447-0.02830.08090.11350.0813-0.11630.482-0.0710.09270.8620.09560.739825.876190.224169.5275
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 375
2X-RAY DIFFRACTION2L1 - 214
3X-RAY DIFFRACTION3H2 - 227
4X-RAY DIFFRACTION4l3 - 212
5X-RAY DIFFRACTION5h2 - 226
6X-RAY DIFFRACTION6B42 - 375

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