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- PDB-7l05: Complex of novel maytansinoid M24 bound to T2R-TTL (two tubulin a... -

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Basic information

Entry
Database: PDB / ID: 7l05
TitleComplex of novel maytansinoid M24 bound to T2R-TTL (two tubulin alpha/beta heterodimers, RB3 stathmin-like domain, and tubulin tyrosine ligase)
Components
  • Stathmin-4
  • Tubulin Tyrosine Ligase
  • Tubulin alpha-1B chain
  • Tubulin beta chain
KeywordsSTRUCTURAL PROTEIN / maytansinoid / tubulin / antibody-drug conjugate
Function / homology
Function and homology information


tubulin-tyrosine ligase activity / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Hedgehog 'off' state / Cilium Assembly / Intraflagellar transport / COPI-dependent Golgi-to-ER retrograde traffic / Carboxyterminal post-translational modifications of tubulin / RHOH GTPase cycle / Sealing of the nuclear envelope (NE) by ESCRT-III / Kinesins ...tubulin-tyrosine ligase activity / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Hedgehog 'off' state / Cilium Assembly / Intraflagellar transport / COPI-dependent Golgi-to-ER retrograde traffic / Carboxyterminal post-translational modifications of tubulin / RHOH GTPase cycle / Sealing of the nuclear envelope (NE) by ESCRT-III / Kinesins / PKR-mediated signaling / The role of GTSE1 in G2/M progression after G2 checkpoint / Aggrephagy / Resolution of Sister Chromatid Cohesion / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / Separation of Sister Chromatids / RHO GTPases activate IQGAPs / RHO GTPases Activate Formins / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / MHC class II antigen presentation / Recruitment of NuMA to mitotic centrosomes / microtubule depolymerization / COPI-mediated anterograde transport / regulation of microtubule polymerization or depolymerization / tubulin binding / spindle microtubule / protein modification process / structural constituent of cytoskeleton / microtubule cytoskeleton organization / microtubule cytoskeleton / neuron projection development / mitotic cell cycle / growth cone / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / microtubule / neuron projection / GTPase activity / nucleotide binding / GTP binding / Golgi apparatus / metal ion binding / cytoplasm
Similarity search - Function
Tubulin-tyrosine ligase/Tubulin polyglutamylase / Tubulin-tyrosine ligase family / TTL domain profile. / Stathmin family / Stathmin, conserved site / Stathmin superfamily / Stathmin family / Stathmin family signature 1. / Stathmin family signature 2. / Stathmin-like (SLD) domain profile. ...Tubulin-tyrosine ligase/Tubulin polyglutamylase / Tubulin-tyrosine ligase family / TTL domain profile. / Stathmin family / Stathmin, conserved site / Stathmin superfamily / Stathmin family / Stathmin family signature 1. / Stathmin family signature 2. / Stathmin-like (SLD) domain profile. / Alpha tubulin / Tubulin-beta mRNA autoregulation signal. / Beta tubulin, autoregulation binding site / Beta tubulin / Tubulin / Tubulin, C-terminal / Tubulin C-terminal domain / Tubulin, conserved site / Tubulin subunits alpha, beta, and gamma signature. / Tubulin/FtsZ family, C-terminal domain / Tubulin/FtsZ-like, C-terminal domain / Tubulin/FtsZ, C-terminal / Tubulin/FtsZ, 2-layer sandwich domain / Tubulin/FtsZ family, GTPase domain / Tubulin/FtsZ family, GTPase domain / Tubulin/FtsZ, GTPase domain / Tubulin/FtsZ, GTPase domain superfamily
Similarity search - Domain/homology
PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / GUANOSINE-5'-DIPHOSPHATE / GUANOSINE-5'-TRIPHOSPHATE / Chem-XQ4 / Tubulin tyrosine ligase / Tubulin beta chain / Stathmin-4 / Tubulin alpha-1B chain
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Gallus gallus (chicken)
Sus scrofa (pig)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.21 Å
AuthorsFranklin, M.C.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Mol.Cancer Ther. / Year: 2021
Title: A Biparatopic Antibody-Drug Conjugate to Treat MET-Expressing Cancers, Including Those that Are Unresponsive to MET Pathway Blockade.
Authors: DaSilva, J.O. / Yang, K. / Surriga, O. / Nittoli, T. / Kunz, A. / Franklin, M.C. / Delfino, F.J. / Mao, S. / Zhao, F. / Giurleo, J.T. / Kelly, M.P. / Makonnen, S. / Hickey, C. / Krueger, P. ...Authors: DaSilva, J.O. / Yang, K. / Surriga, O. / Nittoli, T. / Kunz, A. / Franklin, M.C. / Delfino, F.J. / Mao, S. / Zhao, F. / Giurleo, J.T. / Kelly, M.P. / Makonnen, S. / Hickey, C. / Krueger, P. / Foster, R. / Chen, Z. / Retter, M.W. / Slim, R. / Young, T.M. / Olson, W.C. / Thurston, G. / Daly, C.
History
DepositionDec 11, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._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: Tubulin alpha-1B chain
B: Tubulin beta chain
C: Tubulin alpha-1B chain
D: Tubulin beta chain
E: Stathmin-4
F: Tubulin Tyrosine Ligase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)266,14826
Polymers262,2766
Non-polymers3,87220
Water17,240957
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)105.088, 158.036, 181.014
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
21C
12B
22D

NCS domain segments:

Component-ID: _ / End auth comp-ID: ASP / End label comp-ID: ASP / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11METMETAA1 - 4381 - 438
21METMETCC1 - 4381 - 438
12ARGARGBB2 - 4352 - 427
22ARGARGDD2 - 4352 - 427

NCS ensembles :
ID
1
2

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Components

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Protein , 4 types, 6 molecules ACBDEF

#1: Protein Tubulin alpha-1B chain / Alpha-tubulin ubiquitous / Tubulin K-alpha-1 / Tubulin alpha-ubiquitous chain


Mass: 50204.445 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: Q2XVP4
#2: Protein Tubulin beta chain / Beta-tubulin


Mass: 49907.770 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: P02554
#3: Protein Stathmin-4 / Stathmin-like protein B3 / RB3


Mass: 17673.043 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Stmn4 / Production host: Escherichia coli (E. coli) / References: UniProt: P63043
#4: Protein Tubulin Tyrosine Ligase


Mass: 44378.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: TTL / Production host: Escherichia coli (E. coli) / References: UniProt: E1BQ43

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Non-polymers , 10 types, 977 molecules

#5: Chemical ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE


Mass: 523.180 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Comment: GTP, energy-carrying molecule*YM
#6: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Mg
#7: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#8: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#9: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#10: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#11: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#12: Chemical ChemComp-XQ4 / (1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.1~10,14~.0~3,5~]hexacosa-10(26),11,13,16,18-pentaen-6-yl (2S)-2-{methyl[3-(methylamino)propanoyl]amino}propanoate (non-preferred name)


Mass: 735.264 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H51ClN4O10
#13: Chemical ChemComp-ACP / PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / ADENOSINE-5'-[BETA, GAMMA-METHYLENE]TRIPHOSPHATE


Mass: 505.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H18N5O12P3 / Comment: AMP-PCP, energy-carrying molecule analogue*YM
#14: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 957 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.87 Å3/Da / Density % sol: 57.08 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: PEG 3350, MES, CaCl2, MgCl2, glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Dec 20, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 150790 / % possible obs: 99.4 % / Observed criterion σ(I): -3 / Redundancy: 12.2 % / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.023 / Rrim(I) all: 0.081 / Net I/σ(I): 33
Reflection shellResolution: 2.2→2.24 Å / Redundancy: 9.4 % / Rmerge(I) obs: 0.932 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 7363 / CC1/2: 0.748 / Rpim(I) all: 0.311 / Rrim(I) all: 0.984 / % possible all: 98.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4IHJ

4ihj


Resolution: 2.21→45.62 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.934 / SU B: 9.851 / SU ML: 0.129 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.222 / ESU R Free: 0.178 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2167 7466 5 %RANDOM
Rwork0.1857 ---
obs0.1873 141073 97.75 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 140 Å2 / Biso mean: 39.203 Å2 / Biso min: 11.05 Å2
Baniso -1Baniso -2Baniso -3
1-0.58 Å20 Å2-0 Å2
2---0.37 Å2-0 Å2
3----0.21 Å2
Refinement stepCycle: final / Resolution: 2.21→45.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17281 0 236 957 18474
Biso mean--42.06 40.4 -
Num. residues----2183
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.01318064
X-RAY DIFFRACTIONr_bond_other_d0.0010.01716679
X-RAY DIFFRACTIONr_angle_refined_deg1.5431.65424487
X-RAY DIFFRACTIONr_angle_other_deg1.3451.58338482
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.66352217
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.72522.745980
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.342153040
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.57415109
X-RAY DIFFRACTIONr_chiral_restr0.0770.22343
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0220456
X-RAY DIFFRACTIONr_gen_planes_other0.0010.024167
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A133370.11
12C133370.11
21B134600.07
22D134600.07
LS refinement shellResolution: 2.21→2.262 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.28 454 -
Rwork0.247 8594 -
obs--81.56 %
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)
10.06450.1357-0.00391.09330.88611.15740.02470.0301-0.0183-0.00050.1218-0.0081-0.1530.1425-0.14650.184-0.02630.05810.2279-0.1350.217725.27583.35161.453
20.1231-0.11610.02240.69730.74461.0066-0.00940.00150.0055-0.0256-0.06990.0449-0.0488-0.06560.07930.0917-0.00420.0260.2787-0.12610.245516.36357.38129.604
30.1809-0.00770.12940.50590.44230.5906-0.04680.0190.0297-0.03560.02020.03910.0294-0.00660.02660.1259-0.02730.02030.2414-0.02740.230913.16629.249-3.765
40.3647-0.0639-0.23270.62210.29720.6076-0.14010.1234-0.0453-0.14740.13480.00340.1461-0.06990.00530.2812-0.07810.05370.2725-0.14370.137618.215-1.607-31.922
50.0459-0.2602-0.33392.58112.723.0964-0.0196-0.0236-0.00660.08030.2612-0.28240.11390.3605-0.24160.00880.00070.01330.3535-0.26910.276339.68641.60320.515
60.72570.2011-1.33420.288-0.53082.9854-0.2561-0.0812-0.24870.05290.0288-0.03910.22220.24150.22740.32730.03310.12840.12360.00830.25744.72655.87892.576
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 439
2X-RAY DIFFRACTION2B1 - 436
3X-RAY DIFFRACTION3C1 - 440
4X-RAY DIFFRACTION4D2 - 439
5X-RAY DIFFRACTION5E6 - 141
6X-RAY DIFFRACTION6F1 - 384

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