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- PDB-8er7: FKBP12-FRB in Complex with Compound 12 -

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Basic information

Entry
Database: PDB / ID: 8er7
TitleFKBP12-FRB in Complex with Compound 12
Components
  • Peptidyl-prolyl cis-trans isomerase FKBP1A
  • non-specific serine/threonine protein kinase
KeywordsCOMPLEX (ISOMERASE/KINASE) / Antitumor / mTORC1 / COMPLEX (ISOMERASE-KINASE) complex
Function / homology
Function and homology information


positive regulation of response to stimulus / regulation of nucleobase-containing compound metabolic process / response to chemical / regulation of cellular response to stress / signaling receptor inhibitor activity / macrolide binding / activin receptor binding / TORC1 complex / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / cytoplasmic side of membrane ...positive regulation of response to stimulus / regulation of nucleobase-containing compound metabolic process / response to chemical / regulation of cellular response to stress / signaling receptor inhibitor activity / macrolide binding / activin receptor binding / TORC1 complex / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / cytoplasmic side of membrane / transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / type I transforming growth factor beta receptor binding / negative regulation of activin receptor signaling pathway / heart trabecula formation / I-SMAD binding / regulation of amyloid precursor protein catabolic process / terminal cisterna / ryanodine receptor complex / ventricular cardiac muscle tissue morphogenesis / response to stress / protein maturation by protein folding / 'de novo' protein folding / FK506 binding / channel regulator activity / TGF-beta receptor signaling activates SMADs / mTORC1-mediated signalling / protein peptidyl-prolyl isomerization / Calcineurin activates NFAT / regulation of immune response / regulation of ryanodine-sensitive calcium-release channel activity / heart morphogenesis / supramolecular fiber organization / sarcoplasmic reticulum membrane / positive regulation of protein metabolic process / T cell activation / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / sarcoplasmic reticulum / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / negative regulation of transforming growth factor beta receptor signaling pathway / calcium ion transmembrane transport / Z disc / SARS-CoV-1 activates/modulates innate immune responses / protein folding / positive regulation of protein binding / regulation of protein localization / protein refolding / peptidyl-serine phosphorylation / positive regulation of canonical NF-kappaB signal transduction / transmembrane transporter binding / amyloid fibril formation / Potential therapeutics for SARS / non-specific serine/threonine protein kinase / protein serine/threonine kinase activity / protein-containing complex binding / ATP binding / membrane / cytosol / cytoplasm
Similarity search - Function
FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / PIK-related kinase, FAT / FATC domain / FATC / FAT domain / FAT domain profile. / FATC domain profile. ...FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / PIK-related kinase, FAT / FATC domain / FATC / FAT domain / FAT domain profile. / FATC domain profile. / FATC domain / PIK-related kinase / : / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase / Phosphatidylinositol 3- and 4-kinase / Peptidyl-prolyl cis-trans isomerase domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-XZ3 / non-specific serine/threonine protein kinase / Peptidyl-prolyl cis-trans isomerase FKBP1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.07 Å
AuthorsTomlinson, A.C.A. / Yano, J.K.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
Citation
Journal: J Med Chem / Year: 2023
Title: Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.
Authors: G Leslie Burnett / Yu C Yang / James B Aggen / Jennifer Pitzen / Micah K Gliedt / Chris M Semko / Abby Marquez / James W Evans / Gang Wang / Walter S Won / Aidan C A Tomlinson / Gert Kiss / ...Authors: G Leslie Burnett / Yu C Yang / James B Aggen / Jennifer Pitzen / Micah K Gliedt / Chris M Semko / Abby Marquez / James W Evans / Gang Wang / Walter S Won / Aidan C A Tomlinson / Gert Kiss / Christos Tzitzilonis / Arun P Thottumkara / James Cregg / Kevin T Mellem / Jong S Choi / Julie C Lee / Yongyuan Zhao / Bianca J Lee / Justin G Meyerowitz / John E Knox / Jingjing Jiang / Zhican Wang / David Wildes / Zhengping Wang / Mallika Singh / Jacqueline A M Smith / Adrian L Gill /
Abstract: Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of ...Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRAS shows increased antitumor activity in a preclinical model of mutant NSCLC that exhibits resistance to KRAS inhibitor monotherapy.
History
DepositionOct 11, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 28, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Peptidyl-prolyl cis-trans isomerase FKBP1A
B: non-specific serine/threonine protein kinase
C: Peptidyl-prolyl cis-trans isomerase FKBP1A
D: non-specific serine/threonine protein kinase
E: Peptidyl-prolyl cis-trans isomerase FKBP1A
F: non-specific serine/threonine protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,79911
Polymers69,9386
Non-polymers2,8625
Water724
1
A: Peptidyl-prolyl cis-trans isomerase FKBP1A
B: non-specific serine/threonine protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2433
Polymers23,3132
Non-polymers9301
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Peptidyl-prolyl cis-trans isomerase FKBP1A
D: non-specific serine/threonine protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2784
Polymers23,3132
Non-polymers9662
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
E: Peptidyl-prolyl cis-trans isomerase FKBP1A
F: non-specific serine/threonine protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2784
Polymers23,3132
Non-polymers9662
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)125.080, 125.080, 253.415
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number181
Space group name H-MP6422
Space group name HallP642(x,y,z+1/6)
Symmetry operation#1: x,y,z
#2: x-y,x,z+2/3
#3: y,-x+y,z+1/3
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+2/3
#8: -x,-y,z
#9: y,x,-z+1/3
#10: -y,-x,-z+1/3
#11: -x+y,y,-z
#12: x,x-y,-z+2/3

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Components

#1: Protein Peptidyl-prolyl cis-trans isomerase FKBP1A / PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / FK506-binding ...PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / FK506-binding protein 1A / FKBP-1A / Immunophilin FKBP12 / Rotamase


Mass: 11923.586 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP1A, FKBP1, FKBP12 / Production host: Escherichia coli (E. coli) / References: UniProt: P62942, peptidylprolyl isomerase
#2: Protein non-specific serine/threonine protein kinase


Mass: 11388.987 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MTOR / Production host: Escherichia coli (E. coli)
References: UniProt: B1AKP8, non-specific serine/threonine protein kinase
#3: Chemical ChemComp-XZ3 / (3S,5R,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,30R,34aS)-9,27-dihydroxy-3-{(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl}-5,10,21-trimethoxy-6,8,12,14,20,26-hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontine-1,11,28,29(4H,31H)-tetrone


Mass: 930.214 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C52H83NO13 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 4.09 Å3/Da / Density % sol: 69.94 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 3.0-3.3 M sodium formate and 0.1 M HEPES pH 7.0-7.5
PH range: 7.0-7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.99993 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Oct 23, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99993 Å / Relative weight: 1
ReflectionResolution: 3.07→45.91 Å / Num. obs: 21756 / % possible obs: 95.8 % / Redundancy: 4.2 % / Biso Wilson estimate: 92.86 Å2 / Rrim(I) all: 0.082 / Rsym value: 0.072 / Net I/σ(I): 11.06
Reflection shellResolution: 3.07→3.32 Å / Mean I/σ(I) obs: 2.88 / Num. unique obs: 2054 / Rrim(I) all: 0.0486 / Rsym value: 0.0427

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1FAP

1fap


Resolution: 3.07→45.91 Å / SU ML: 0.3504 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 32.8029
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2786 489 2.25 %
Rwork0.2411 21250 -
obs0.242 21739 95.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 119.85 Å2
Refinement stepCycle: LAST / Resolution: 3.07→45.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4903 0 200 4 5107
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01265233
X-RAY DIFFRACTIONf_angle_d1.49787062
X-RAY DIFFRACTIONf_chiral_restr0.0795737
X-RAY DIFFRACTIONf_plane_restr0.0048906
X-RAY DIFFRACTIONf_dihedral_angle_d16.28072024
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.07-3.510.36441590.32497005X-RAY DIFFRACTION97.22
3.51-4.430.28881610.25327131X-RAY DIFFRACTION97.75
4.43-45.910.25041690.21437114X-RAY DIFFRACTION92.79
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)
11.48665196844-1.42003909312-0.4603513968551.39593875310.1375650846322.29652989974-0.586904826218-0.00456937332266-0.4573952866660.2525371352180.187500161673-0.8623289138551.267284785520.411106186597-1.61605472671E-81.466564913420.08799131514660.1817882646560.84658957091-0.0578809475971.40574589438-24.80585546515.41326559240.2679725178
22.711196145162.15783370292-1.358457235523.614173791030.5550971764293.08649962291-0.4271088625020.09736740126130.0151650596195-0.4195985133140.384187743783-0.2704456958370.2775045391940.507416447741-1.3584693338E-80.932000512038-0.0634676616659-0.004291567774620.832745024570.016241041520.904276453897-26.700371372440.76919243610.757592123639
35.731991189282.023458165921.898792150751.825464304180.05030881043781.249683253260.0773334947274-0.279310252116-0.02596237082580.0009693984546920.039673012362-0.22508554028-0.08387555316720.0524613180205-3.48840910912E-81.31201122172-0.0546861935140.2235981632050.825488589154-0.01669131714140.993286427576-47.500151306516.4617410238-18.9020397978
44.21568906454-2.14088638229-0.7948425323641.974123528881.258118112130.9610511062020.1103229013620.3663822775440.000385013901572-0.321617202485-0.1797028100590.105089848498-0.0749495648779-0.475830565964-2.60018223038E-81.3313144276-0.0270884542630.1258040873720.8788445532240.05696753113560.997949197272-72.526276131320.6702529353-21.0530801161
53.131654407860.46896776726-0.4473363930965.251740038031.513248817014.165378565270.456755185443-0.1825598821710.292360602890.350178739017-0.0375270691773-0.388272085695-0.8547643205611.950491310220.007736721128670.919187279323-0.07035986267010.03143067981191.87963903053-0.2197965140010.981256507131-61.38104708353.126697927-37.9200048295
66.949769853190.423856140381-1.173209846074.064090022980.974848719392.96264090042-0.2559730008510.45510173055-0.4213667320160.3845805066430.435798688652-0.39661743116-0.09720712211330.8869171055567.23177336265E-90.878800558328-0.0680262734087-0.02698461289761.16793187179-0.2527170436870.925670929412-68.979591901451.6949757656-13.9560823763
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 1:108 )A1 - 108
2X-RAY DIFFRACTION2( CHAIN B AND RESID 2018:2112 )B2018 - 2112
3X-RAY DIFFRACTION3( CHAIN C AND RESID 1:108 )C1 - 108
4X-RAY DIFFRACTION4( CHAIN D AND RESID 2019:2112 )D2019 - 2112
5X-RAY DIFFRACTION5( CHAIN E AND RESID 2:108 )E2 - 108
6X-RAY DIFFRACTION6( CHAIN F AND RESID 2018:2112 )F2018 - 2112

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