PDB-8chk: Human FKBP12 in complex with (1S,5S,6R)-10-((S)-(3,5-dichlorophen...

ID or keywords:

Entry

Database: PDB / ID: 8chk

Title

Human FKBP12 in complex with (1S,5S,6R)-10-((S)-(3,5-dichlorophenyl)sulfonimidoyl)-3-(pyridin-2-ylmethyl)-5-vinyl-3,10-diazabicyclo[4.3.1]decan-2-one

Components

Peptidyl-prolyl cis-trans isomerase FKBP1A

Keywords

ISOMERASE / FKBP12 / Inhibitor

Function / homology

Function and homology information

macrolide binding / activin receptor binding / 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 ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.55 Å

Authors

Meyners, C. / Purder, P.L. / Hausch, F.

Funding support

Germany, 1items

Citation

Journal: Jacs Au / Year: 2023
Title: Deconstructing Protein Binding of Sulfonamides and Sulfonamide Analogues.
Authors: Purder, P.L. / Meyners, C. / Sugiarto, W.O. / Kolos, J. / Lohr, F. / Gebel, J. / Nehls, T. / Dotsch, V. / Lermyte, F. / Hausch, F.

History

Deposition	Feb 8, 2023	Deposition site: PDBE / Processing site: PDBE
Revision 1.0	Sep 6, 2023	Provider: repository / Type: Initial release
Revision 1.1	Oct 11, 2023	Group: Database references / Category: citation Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

Structure viewer	Molecule: MolmilJmol/JSmol

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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/ch/8chk ftp://data.pdbj.org/pub/pdb/validation_reports/ch/8chk	HTTPS FTP

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Related structure data

Related structure data	8chiC 8chjC 8chlC 8chmC 8chnC 8chpC 8chqC 8chrC 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

B: Peptidyl-prolyl cis-trans isomerase FKBP1A

C: Peptidyl-prolyl cis-trans isomerase FKBP1A

hetero molecules

37.3 kDa, 3 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

A: Peptidyl-prolyl cis-trans isomerase FKBP1A

hetero molecules

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

2

B: Peptidyl-prolyl cis-trans isomerase FKBP1A

hetero molecules

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

3

C: Peptidyl-prolyl cis-trans isomerase FKBP1A

hetero molecules

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

Unit cell

Length a, b, c (Å)	44.874, 53.416, 124.974
Angle α, β, γ (deg.)	90.000, 90.000, 90.000
Int Tables number	19
Space group name H-M	P2₁2₁2₁

Noncrystallographic symmetry (NCS)

NCS domain:

ID	Ens-ID	Details
1	1	A
2	1	A
3	2	A
4	2	A
5	3	A
6	3	A

NCS domain segments:

Beg auth comp-ID: GLY / Beg label comp-ID: GLY / End auth comp-ID: GLU / End label comp-ID: GLU / Auth asym-ID: A / Label asym-ID: A / Auth seq-ID: 1 - 107 / Label seq-ID: 1 - 107

Dom-ID	Component-ID	Ens-ID
1	1	1
2	1	1
3	2	2
4	2	2
5	3	3
6	3	3

NCS ensembles :

ID	Details
1	Local NCS retraints between domains: 1 2
2	Local NCS retraints between domains: 3 4
3	Local NCS retraints between domains: 5 6

#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.: 3 / Mutation: C22V 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-UUI / (1S,5S,6R)-10-[[3,5-bis(chloranyl)phenyl]sulfonimidoyl]-5-ethenyl-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one Mass: 479.423 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C₂₂H₂₄Cl₂N₄O₂S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical	ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID Mass: 195.237 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₆H₁₃NO₄S / Comment: pH buffer*YM
#4: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 279 / 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: 2.11 Å³/Da / Density % sol: 41.7 %
Crystal grow	Temperature: 293 K / Method: vapor diffusion, hanging drop Details: 1.32M Na-K tartrate, 0.2 M 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: 14.1 / Wavelength: 0.9184 Å

Detector

Type: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Sep 23, 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: 1.55→49.166 Å / Num. obs: 44140 / % possible obs: 98.9 % / Redundancy: 6.1 % / CC_1/2: 0.998 / R_merge(I) obs: 0.104 / R_pim(I) all: 0.066 / R_rim(I) all: 0.124 / Net I/σ(I): 10.8

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
8.48-49.12	5.5	0.022	340	0.999	0.014	0.026
1.55-1.58	5.2	1.501	1971	0.345	0.978	1.801

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0403	refinement
XDS		data reduction
Aimless		data scaling
PHASER		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.55→49.166 Å / Cor.coef. F_o:F_c: 0.961 / Cor.coef. F_o:F_c free: 0.949 / SU B: 5.45 / SU ML: 0.092 / Cross valid method: THROUGHOUT / ESU R: 0.096 / ESU R Free: 0.097
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2328	2206	5.006 %
R_work	0.1967	41864	-
all	0.198	-	-
obs	-	44070	98.98 %

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: 18.287 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-1.89 Å²	-0 Å²	0 Å²
2-	-	0.328 Å²	-0 Å²
3-	-	-	1.562 Å²

Refinement step

Cycle: LAST / Resolution: 1.55→49.166 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	2473	0	117	279	2869

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.013	0.012	2676
X-RAY DIFFRACTION	r_bond_other_d	0.004	0.016	2500
X-RAY DIFFRACTION	r_angle_refined_deg	1.731	1.71	3635
X-RAY DIFFRACTION	r_angle_other_deg	0.789	1.622	5780
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	7.368	5	322
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	9.959	5	17
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	13.917	10	425
X-RAY DIFFRACTION	r_dihedral_angle_6_deg	15.821	10	112
X-RAY DIFFRACTION	r_chiral_restr	0.132	0.2	390
X-RAY DIFFRACTION	r_chiral_restr_other	1.498	0.2	15
X-RAY DIFFRACTION	r_gen_planes_refined	0.01	0.02	3084
X-RAY DIFFRACTION	r_gen_planes_other	0.001	0.02	601
X-RAY DIFFRACTION	r_nbd_refined	0.202	0.2	410
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.198	0.2	2290
X-RAY DIFFRACTION	r_nbtor_refined	0.181	0.2	1293
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.087	0.2	1412
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.178	0.2	205
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.152	0.2	17
X-RAY DIFFRACTION	r_nbd_other	0.229	0.2	99
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.217	0.2	21
X-RAY DIFFRACTION	r_mcbond_it	1.254	1.346	1300
X-RAY DIFFRACTION	r_mcbond_other	1.253	1.346	1299
X-RAY DIFFRACTION	r_mcangle_it	1.717	2.412	1618
X-RAY DIFFRACTION	r_mcangle_other	1.717	2.412	1619
X-RAY DIFFRACTION	r_scbond_it	2.25	1.631	1376
X-RAY DIFFRACTION	r_scbond_other	2.251	1.63	1374
X-RAY DIFFRACTION	r_scangle_it	3.421	2.881	2017
X-RAY DIFFRACTION	r_scangle_other	3.42	2.881	2018
X-RAY DIFFRACTION	r_lrange_it	4.882	16.856	2934
X-RAY DIFFRACTION	r_lrange_other	4.789	15.422	2870
X-RAY DIFFRACTION	r_ncsr_local_group_1	0.12	0.05	3166
X-RAY DIFFRACTION	r_ncsr_local_group_2	0.133	0.05	3039
X-RAY DIFFRACTION	r_ncsr_local_group_3	0.129	0.05	3035

Refine LS restraints NCS

Ens-ID	Dom-ID	Auth asym-ID	Refine-ID	Type	Rms dev position (Å)	Weight position
1	1	A	X-RAY DIFFRACTION	Local ncs	0.11952	0.05008
1	2	A	X-RAY DIFFRACTION	Local ncs	0.11952	0.05008
2	3	A	X-RAY DIFFRACTION	Local ncs	0.13326	0.05007
2	4	A	X-RAY DIFFRACTION	Local ncs	0.13326	0.05007
3	5	A	X-RAY DIFFRACTION	Local ncs	0.12912	0.05008
3	6	A	X-RAY DIFFRACTION	Local ncs	0.12912	0.05008

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
1.55-1.59	0.318	150	0.342	2891	0.341	3209	0.919	0.901	94.7647	0.339
1.59-1.633	0.347	184	0.326	2886	0.327	3164	0.891	0.902	97.0291	0.318
1.633-1.681	0.301	157	0.309	2848	0.308	3078	0.906	0.912	97.6283	0.299
1.681-1.732	0.308	138	0.278	2869	0.279	3014	0.921	0.933	99.7678	0.261
1.732-1.789	0.322	152	0.264	2759	0.267	2912	0.912	0.941	99.9657	0.248
1.789-1.852	0.307	139	0.243	2635	0.246	2776	0.931	0.953	99.928	0.223
1.852-1.921	0.247	130	0.221	2567	0.222	2701	0.95	0.963	99.8519	0.198
1.921-2	0.227	137	0.203	2455	0.205	2630	0.958	0.969	98.5551	0.182
2-2.089	0.214	125	0.184	2374	0.185	2505	0.969	0.977	99.7605	0.163
2.089-2.19	0.232	125	0.178	2287	0.18	2414	0.962	0.977	99.9172	0.159
2.19-2.308	0.222	122	0.181	2174	0.183	2301	0.968	0.977	99.7827	0.163
2.308-2.448	0.25	101	0.17	2079	0.174	2181	0.965	0.981	99.9542	0.152
2.448-2.617	0.225	100	0.195	1950	0.196	2055	0.97	0.979	99.7567	0.178
2.617-2.826	0.274	90	0.217	1824	0.22	1934	0.959	0.974	98.9659	0.195
2.826-3.094	0.229	82	0.197	1672	0.198	1755	0.968	0.975	99.943	0.181
3.094-3.458	0.21	77	0.175	1545	0.177	1622	0.972	0.98	100	0.169
3.458-3.99	0.177	65	0.147	1379	0.148	1446	0.984	0.987	99.8617	0.146
3.99-4.878	0.155	65	0.126	1169	0.128	1236	0.987	0.99	99.8382	0.129
4.878-6.865	0.198	43	0.154	930	0.156	983	0.979	0.986	98.9827	0.158
6.865-49.166	0.225	24	0.217	571	0.217	598	0.98	0.966	99.4983	0.224

Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

ID	L11 (°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)
1	0.2813	0.0195	0.0435	1.5057	-1.2045	2.1456	0.0183	-0.0185	0.0129	-0.0987	-0.0078	0.0519	0.0033	-0.0333	-0.0106	0.0155	0.0004	0.0024	0.0031	-0.0059	0.0238	-3.9164	-10.2809	14.3469
2	1	0.0756	0.1212	2.0365	-0.5416	1.8225	0.0451	0.0575	-0.0103	-0.1318	-0.0337	-0.0512	0.1544	0.1414	-0.0114	0.0294	0.0268	-0.0024	0.03	-0.0073	0.0085	12.668	-31.6954	11.1793
3	3.2233	-0.2145	-0.8574	0.535	0.0621	0.8041	0.005	0.0648	0.0553	0.0025	-0.0196	0.0046	-0.0447	-0.0493	0.0146	0.0245	-0.0064	-0.0072	0.0072	0.0008	0.0072	17.2145	-13.2233	36.1972

Refinement TLS group

Selection: ALL

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