PDB-8pdf: FKBP12 in complex with PROTAC 6a2

ID or keywords:

Entry

Database: PDB / ID: 8pdf

Title

FKBP12 in complex with PROTAC 6a2

Components

Peptidyl-prolyl cis-trans isomerase FKBP1A

Keywords

ISOMERASE / FKBP12 / Complex / PROTAC

Function / homology

Function and homology information

macrolide binding / activin receptor binding / cytoplasmic side of membrane / signaling receptor inhibitor activity / 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 / terminal cisterna ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.2 Å

Authors

Meyners, C. / Walz, M. / Geiger, T.M. / Hausch, F.

Funding support

Germany, 1items

Citation

Journal: Angew.Chem.Int.Ed.Engl. / Year: 2024
Title: Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506-Binding Protein 51 (FKBP51).
Authors: Geiger, T.M. / Walz, M. / Meyners, C. / Kuehn, A. / Dreizler, J.K. / Sugiarto, W.O. / Maciel, E.V.S. / Zheng, M. / Lermyte, F. / Hausch, F.

History

Deposition	Jun 12, 2023	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Nov 15, 2023	Provider: repository / Type: Initial release
Revision 1.1	Nov 22, 2023	Group: Database references / Category: citation Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2	Dec 27, 2023	Group: Database references / Category: citation / citation_author Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3	Jan 17, 2024	Group: 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 1.4	Jan 24, 2024	Group: Database references / Category: citation / citation_author Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

Structure viewer	Molecule: MolmilJmol/JSmol

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Related structure data

Related structure data	8pc2C C: citing same article (ref.)
Similar structure data	Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#230 - Feb 2019 Initiation Factor eIF4E similarity (1) #60 - Dec 2004 Ubiquitin similarity (2) #44 - Aug 2003 Calmodulin similarity (1) #163 - Jul 2013 HIV Capsid similarity (2) #196 - Apr 2016 Lead Poisoning similarity (1) #28 - Apr 2002 Anthrax Toxin similarity (1) #234 - Jun 2019 MDM2 and Cancer similarity (1) #245 - May 2020 Spliceosomes similarity (1)

Deposited unit

A: Peptidyl-prolyl cis-trans isomerase FKBP1A

hetero molecules

12.9 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author

Unit cell

Length a, b, c (Å)	65.993, 36.506, 44.217
Angle α, β, γ (deg.)	90.000, 102.186, 90.000
Int Tables number	5
Space group name H-M	C121

#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: 11832.496 Da / Num. of mol.: 1 / Mutation: C23V Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP1A, FKBP1, FKBP12 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P62942, peptidylprolyl isomerase
#2: Chemical	ChemComp-Y5Q / (2~{S},4~{R})-1-[(2~{S})-2-[2-[2-[2-[4-[(1~{S})-1-[(1~{S},5~{S},6~{R})-10-[3,5-bis(chloranyl)phenyl]sulfonyl-5-ethenyl-2-oxidanylidene-3,10-diazabicyclo[4.3.1]decan-3-yl]ethyl]-1,2,3-triazol-1-yl]ethoxy]ethoxy]ethanoylamino]-3,3-dimethyl-butanoyl]-~{N}-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]-4-oxidanyl-pyrrolidine-2-carboxamide Mass: 1043.089 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₄₈H₆₁Cl₂N₉O₉S₂ / Feature type: SUBJECT OF INVESTIGATION
#3: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 152 / Source method: isolated from a natural source / Formula: H₂O
Has ligand of interest	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.2 Å³/Da / Density % sol: 44.09 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion, hanging drop Details: 1.36 Na/K tartrate, 0.2M ammonium citrate, 0.1M MES pH 6.5

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Data collection

Diffraction

Mean temperature: 100 K / Serial crystal experiment: N

Diffraction source

Source:

SYNCHROTRON / Site:

BESSY

/ Beamline: 14.2 / Wavelength: 0.9184 Å

Detector

Type: DECTRIS PILATUS3 S 2M / Detector: PIXEL / Date: Jul 17, 2021

Radiation

Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray

Radiation wavelength

Wavelength: 0.9184 Å / Relative weight: 1

Reflection

Resolution: 1.2→43.22 Å / Num. obs: 32330 / % possible obs: 99.9 % / Redundancy: 6.3 % / CC_1/2: 0.999 / R_merge(I) obs: 0.055 / R_pim(I) all: 0.036 / R_rim(I) all: 0.066 / Net I/σ(I): 11.7

Reflection shell

Diffraction-ID: 1

Resolution (Å)	Redundancy (%)	R_merge(I) obs	Num. unique obs	CC_1/2	R_pim(I) all	R_rim(I) all
6.57-43.22	5.8	0.039	220	0.998	0.025	0.046
1.2-1.22	6	1.318	1625	0.625	0.892	1.599

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0411	refinement
XDS		data reduction
Aimless		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.2→31.791 Å / Cor.coef. F_o:F_c: 0.981 / Cor.coef. F_o:F_c free: 0.977 / SU B: 1.994 / SU ML: 0.038 / Cross valid method: THROUGHOUT / ESU R: 0.041 / ESU R Free: 0.04
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.1756	1615	4.996 %
R_work	0.1516	30709	-
all	0.153	-	-
obs	-	32324	99.91 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 17.843 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	1.127 Å²	0 Å²	0.489 Å²
2-	-	-0.995 Å²	-0 Å²
3-	-	-	-0.314 Å²

Refinement step

Cycle: LAST / Resolution: 1.2→31.791 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	820	0	70	152	1042

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.017	0.013	937
X-RAY DIFFRACTION	r_bond_other_d	0.006	0.017	867
X-RAY DIFFRACTION	r_angle_refined_deg	1.969	1.774	1279
X-RAY DIFFRACTION	r_angle_other_deg	1.159	1.697	2002
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	7.191	5	110
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	6.487	5	6
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	13.366	10	140
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	16.602	10	37
X-RAY DIFFRACTION	r_chiral_restr	0.307	0.2	135
X-RAY DIFFRACTION	r_chiral_restr_other	1.576	0.2	17
X-RAY DIFFRACTION	r_gen_planes_refined	0.011	0.02	1078
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	208
X-RAY DIFFRACTION	r_nbd_refined	0.218	0.2	143
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.213	0.2	791
X-RAY DIFFRACTION	r_nbtor_refined	0.176	0.2	437
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.087	0.2	469
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.168	0.2	93
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.188	0.2	22
X-RAY DIFFRACTION	r_nbd_other	0.167	0.2	46
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.25	0.2	19
X-RAY DIFFRACTION	r_mcbond_it	1.392	1.821	440
X-RAY DIFFRACTION	r_mcbond_other	1.392	1.821	440
X-RAY DIFFRACTION	r_mcangle_it	1.815	3.286	550
X-RAY DIFFRACTION	r_mcangle_other	1.813	3.284	551
X-RAY DIFFRACTION	r_scbond_it	1.776	2.056	497
X-RAY DIFFRACTION	r_scbond_other	1.774	2.055	498
X-RAY DIFFRACTION	r_scangle_it	2.314	3.657	729
X-RAY DIFFRACTION	r_scangle_other	2.314	3.655	729
X-RAY DIFFRACTION	r_lrange_it	3.892	25.212	1064
X-RAY DIFFRACTION	r_lrange_other	3.127	21.868	1017
X-RAY DIFFRACTION	r_rigid_bond_restr	4.118	3	1804

LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	R_factor all	Num. reflection all	Fsc free	Fsc work	% reflection obs (%)	WR_factor R_work
1.2-1.231	0.313	115	0.284	2275	0.286	2390	0.916	0.927	100	0.285
1.231-1.265	0.259	110	0.263	2187	0.262	2297	0.936	0.94	100	0.259
1.265-1.301	0.272	113	0.246	2165	0.248	2279	0.932	0.948	99.9561	0.239
1.301-1.341	0.24	102	0.221	2085	0.222	2187	0.958	0.958	100	0.206
1.341-1.385	0.206	97	0.193	2017	0.194	2114	0.971	0.97	100	0.176
1.385-1.434	0.234	93	0.179	1936	0.182	2029	0.966	0.976	100	0.16
1.434-1.488	0.251	85	0.165	1887	0.169	1972	0.963	0.98	100	0.147
1.488-1.548	0.218	105	0.145	1811	0.149	1919	0.963	0.985	99.8437	0.126
1.548-1.617	0.173	94	0.12	1734	0.122	1828	0.98	0.991	100	0.105
1.617-1.696	0.133	90	0.113	1670	0.115	1761	0.989	0.992	99.9432	0.101
1.696-1.787	0.189	110	0.128	1568	0.132	1678	0.978	0.99	100	0.117
1.787-1.895	0.166	85	0.13	1490	0.132	1576	0.98	0.989	99.9366	0.126
1.895-2.026	0.179	86	0.136	1403	0.138	1490	0.981	0.989	99.9329	0.135
2.026-2.187	0.147	73	0.134	1317	0.135	1390	0.987	0.99	100	0.136
2.187-2.395	0.174	57	0.14	1214	0.142	1272	0.984	0.988	99.9214	0.148
2.395-2.676	0.174	60	0.148	1103	0.149	1164	0.98	0.987	99.9141	0.161
2.676-3.086	0.194	44	0.147	974	0.15	1026	0.98	0.986	99.2203	0.171
3.086-3.771	0.172	40	0.145	843	0.146	890	0.979	0.987	99.2135	0.175
3.771-5.295	0.113	41	0.126	645	0.125	686	0.994	0.992	100	0.163
5.295-31.791	0.222	15	0.203	385	0.203	403	0.976	0.974	99.2556	0.251

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