1M63

Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes

Functional Information from GO Data

Chain	GOid	namespace	contents
A	0016787	molecular_function	hydrolase activity
A	0033192	molecular_function	calmodulin-dependent protein phosphatase activity
A	0097720	biological_process	calcineurin-mediated signaling
B	0001569	biological_process	branching involved in blood vessel morphogenesis
B	0001837	biological_process	epithelial to mesenchymal transition
B	0004721	molecular_function	phosphoprotein phosphatase activity
B	0004723	molecular_function	calcium-dependent protein serine/threonine phosphatase activity
B	0005509	molecular_function	calcium ion binding
B	0005515	molecular_function	protein binding
B	0005516	molecular_function	calmodulin binding
B	0005654	cellular_component	nucleoplasm
B	0005737	cellular_component	cytoplasm
B	0005829	cellular_component	cytosol
B	0005886	cellular_component	plasma membrane
B	0005955	cellular_component	calcineurin complex
B	0006606	biological_process	protein import into nucleus
B	0007507	biological_process	heart development
B	0008287	cellular_component	protein serine/threonine phosphatase complex
B	0008597	molecular_function	calcium-dependent protein serine/threonine phosphatase regulator activity
B	0014044	biological_process	Schwann cell development
B	0016018	molecular_function	cyclosporin A binding
B	0016020	cellular_component	membrane
B	0019902	molecular_function	phosphatase binding
B	0019904	molecular_function	protein domain specific binding
B	0022011	biological_process	myelination in peripheral nervous system
B	0033173	biological_process	calcineurin-NFAT signaling cascade
B	0034504	biological_process	protein localization to nucleus
B	0042383	cellular_component	sarcolemma
B	0045202	cellular_component	synapse
B	0045944	biological_process	positive regulation of transcription by RNA polymerase II
B	0046872	molecular_function	metal ion binding
B	0060487	biological_process	lung epithelial cell differentiation
B	0070886	biological_process	positive regulation of calcineurin-NFAT signaling cascade
B	0097720	biological_process	calcineurin-mediated signaling
B	0098685	cellular_component	Schaffer collateral - CA1 synapse
B	0098686	cellular_component	hippocampal mossy fiber to CA3 synapse
B	0098688	cellular_component	parallel fiber to Purkinje cell synapse
B	0098693	biological_process	regulation of synaptic vesicle cycle
B	0098794	cellular_component	postsynapse
B	0098978	cellular_component	glutamatergic synapse
B	0099149	biological_process	regulation of postsynaptic neurotransmitter receptor internalization
B	0099170	biological_process	postsynaptic modulation of chemical synaptic transmission
B	1905665	biological_process	positive regulation of calcium ion import across plasma membrane
B	1905949	biological_process	negative regulation of calcium ion import across plasma membrane
C	0000413	biological_process	protein peptidyl-prolyl isomerization
C	0001666	biological_process	response to hypoxia
C	0001933	biological_process	negative regulation of protein phosphorylation
C	0001934	biological_process	positive regulation of protein phosphorylation
C	0003723	molecular_function	RNA binding
C	0003755	molecular_function	peptidyl-prolyl cis-trans isomerase activity
C	0005178	molecular_function	integrin binding
C	0005515	molecular_function	protein binding
C	0005576	cellular_component	extracellular region
C	0005615	cellular_component	extracellular space
C	0005634	cellular_component	nucleus
C	0005737	cellular_component	cytoplasm
C	0005829	cellular_component	cytosol
C	0005925	cellular_component	focal adhesion
C	0006457	biological_process	protein folding
C	0006469	biological_process	negative regulation of protein kinase activity
C	0006915	biological_process	apoptotic process
C	0016018	molecular_function	cyclosporin A binding
C	0016020	cellular_component	membrane
C	0016853	molecular_function	isomerase activity
C	0019076	biological_process	viral release from host cell
C	0030168	biological_process	platelet activation
C	0030182	biological_process	neuron differentiation
C	0030593	biological_process	neutrophil chemotaxis
C	0030595	biological_process	leukocyte chemotaxis
C	0031982	cellular_component	vesicle
C	0032148	biological_process	activation of protein kinase B activity
C	0032873	biological_process	negative regulation of stress-activated MAPK cascade
C	0032991	cellular_component	protein-containing complex
C	0034389	biological_process	lipid droplet organization
C	0034599	biological_process	cellular response to oxidative stress
C	0034774	cellular_component	secretory granule lumen
C	0035307	biological_process	positive regulation of protein dephosphorylation
C	0042118	biological_process	endothelial cell activation
C	0043231	cellular_component	intracellular membrane-bounded organelle
C	0043410	biological_process	positive regulation of MAPK cascade
C	0045069	biological_process	regulation of viral genome replication
C	0045070	biological_process	positive regulation of viral genome replication
C	0046790	molecular_function	virion binding
C	0050714	biological_process	positive regulation of protein secretion
C	0051082	molecular_function	unfolded protein binding
C	0051092	biological_process	positive regulation of NF-kappaB transcription factor activity
C	0060352	biological_process	cell adhesion molecule production
C	0061944	biological_process	negative regulation of protein K48-linked ubiquitination
C	0070062	cellular_component	extracellular exosome
C	0070527	biological_process	platelet aggregation
C	1902176	biological_process	negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
C	1903901	biological_process	negative regulation of viral life cycle
C	1904399	molecular_function	heparan sulfate binding
C	1904813	cellular_component	ficolin-1-rich granule lumen
C	2001233	biological_process	regulation of apoptotic signaling pathway
E	0016787	molecular_function	hydrolase activity
E	0033192	molecular_function	calmodulin-dependent protein phosphatase activity
E	0097720	biological_process	calcineurin-mediated signaling
F	0001569	biological_process	branching involved in blood vessel morphogenesis
F	0001837	biological_process	epithelial to mesenchymal transition
F	0004721	molecular_function	phosphoprotein phosphatase activity
F	0004723	molecular_function	calcium-dependent protein serine/threonine phosphatase activity
F	0005509	molecular_function	calcium ion binding
F	0005515	molecular_function	protein binding
F	0005516	molecular_function	calmodulin binding
F	0005654	cellular_component	nucleoplasm
F	0005737	cellular_component	cytoplasm
F	0005829	cellular_component	cytosol
F	0005886	cellular_component	plasma membrane
F	0005955	cellular_component	calcineurin complex
F	0006606	biological_process	protein import into nucleus
F	0007507	biological_process	heart development
F	0008287	cellular_component	protein serine/threonine phosphatase complex
F	0008597	molecular_function	calcium-dependent protein serine/threonine phosphatase regulator activity
F	0014044	biological_process	Schwann cell development
F	0016018	molecular_function	cyclosporin A binding
F	0016020	cellular_component	membrane
F	0019902	molecular_function	phosphatase binding
F	0019904	molecular_function	protein domain specific binding
F	0022011	biological_process	myelination in peripheral nervous system
F	0033173	biological_process	calcineurin-NFAT signaling cascade
F	0034504	biological_process	protein localization to nucleus
F	0042383	cellular_component	sarcolemma
F	0045202	cellular_component	synapse
F	0045944	biological_process	positive regulation of transcription by RNA polymerase II
F	0046872	molecular_function	metal ion binding
F	0060487	biological_process	lung epithelial cell differentiation
F	0070886	biological_process	positive regulation of calcineurin-NFAT signaling cascade
F	0097720	biological_process	calcineurin-mediated signaling
F	0098685	cellular_component	Schaffer collateral - CA1 synapse
F	0098686	cellular_component	hippocampal mossy fiber to CA3 synapse
F	0098688	cellular_component	parallel fiber to Purkinje cell synapse
F	0098693	biological_process	regulation of synaptic vesicle cycle
F	0098794	cellular_component	postsynapse
F	0098978	cellular_component	glutamatergic synapse
F	0099149	biological_process	regulation of postsynaptic neurotransmitter receptor internalization
F	0099170	biological_process	postsynaptic modulation of chemical synaptic transmission
F	1905665	biological_process	positive regulation of calcium ion import across plasma membrane
F	1905949	biological_process	negative regulation of calcium ion import across plasma membrane
G	0000413	biological_process	protein peptidyl-prolyl isomerization
G	0001666	biological_process	response to hypoxia
G	0001933	biological_process	negative regulation of protein phosphorylation
G	0001934	biological_process	positive regulation of protein phosphorylation
G	0003723	molecular_function	RNA binding
G	0003755	molecular_function	peptidyl-prolyl cis-trans isomerase activity
G	0005178	molecular_function	integrin binding
G	0005515	molecular_function	protein binding
G	0005576	cellular_component	extracellular region
G	0005615	cellular_component	extracellular space
G	0005634	cellular_component	nucleus
G	0005737	cellular_component	cytoplasm
G	0005829	cellular_component	cytosol
G	0005925	cellular_component	focal adhesion
G	0006457	biological_process	protein folding
G	0006469	biological_process	negative regulation of protein kinase activity
G	0006915	biological_process	apoptotic process
G	0016018	molecular_function	cyclosporin A binding
G	0016020	cellular_component	membrane
G	0016853	molecular_function	isomerase activity
G	0019076	biological_process	viral release from host cell
G	0030168	biological_process	platelet activation
G	0030182	biological_process	neuron differentiation
G	0030593	biological_process	neutrophil chemotaxis
G	0030595	biological_process	leukocyte chemotaxis
G	0031982	cellular_component	vesicle
G	0032148	biological_process	activation of protein kinase B activity
G	0032873	biological_process	negative regulation of stress-activated MAPK cascade
G	0032991	cellular_component	protein-containing complex
G	0034389	biological_process	lipid droplet organization
G	0034599	biological_process	cellular response to oxidative stress
G	0034774	cellular_component	secretory granule lumen
G	0035307	biological_process	positive regulation of protein dephosphorylation
G	0042118	biological_process	endothelial cell activation
G	0043231	cellular_component	intracellular membrane-bounded organelle
G	0043410	biological_process	positive regulation of MAPK cascade
G	0045069	biological_process	regulation of viral genome replication
G	0045070	biological_process	positive regulation of viral genome replication
G	0046790	molecular_function	virion binding
G	0050714	biological_process	positive regulation of protein secretion
G	0051082	molecular_function	unfolded protein binding
G	0051092	biological_process	positive regulation of NF-kappaB transcription factor activity
G	0060352	biological_process	cell adhesion molecule production
G	0061944	biological_process	negative regulation of protein K48-linked ubiquitination
G	0070062	cellular_component	extracellular exosome
G	0070527	biological_process	platelet aggregation
G	1902176	biological_process	negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
G	1903901	biological_process	negative regulation of viral life cycle
G	1904399	molecular_function	heparan sulfate binding
G	1904813	cellular_component	ficolin-1-rich granule lumen
G	2001233	biological_process	regulation of apoptotic signaling pathway

Functional Information from PDB Data

site_id	AC1
Number of Residues	5
Details	BINDING SITE FOR RESIDUE CA B 500

Chain	Residue
B	ASP30
B	ASP32
B	SER34
B	SER36
B	GLU41

---

site_id	AC2
Number of Residues	6
Details	BINDING SITE FOR RESIDUE CA B 501

Chain	Residue
B	ASP70
B	GLU73
B	ASP62
B	ASP64
B	ASN66
B	GLU68

---

site_id	AC3
Number of Residues	5
Details	BINDING SITE FOR RESIDUE CA B 502

Chain	Residue
B	ASP99
B	ASP101
B	ASP103
B	TYR105
B	GLU110

---

site_id	AC4
Number of Residues	5
Details	BINDING SITE FOR RESIDUE CA B 503

Chain	Residue
B	ASP140
B	ASP142
B	ASP144
B	ARG146
B	GLU151

---

site_id	AC5
Number of Residues	5
Details	BINDING SITE FOR RESIDUE ZN A 504

Chain	Residue
A	ASP118
A	ASN150
A	HIS199
A	HIS281
A	FE505

---

site_id	AC6
Number of Residues	5
Details	BINDING SITE FOR RESIDUE FE A 505

Chain	Residue
A	ASP90
A	HIS92
A	ASP118
A	HIS281
A	ZN504

---

site_id	AC7
Number of Residues	5
Details	BINDING SITE FOR RESIDUE CA F 500

Chain	Residue
F	ASP30
F	ASP32
F	SER34
F	SER36
F	GLU41

---

site_id	AC8
Number of Residues	6
Details	BINDING SITE FOR RESIDUE CA F 501

Chain	Residue
F	ASP62
F	ASP64
F	ASN66
F	GLU68
F	ASP70
F	GLU73

---

site_id	AC9
Number of Residues	5
Details	BINDING SITE FOR RESIDUE CA F 502

Chain	Residue
F	ASP99
F	ASP101
F	ASP103
F	TYR105
F	GLU110

---

site_id	BC1
Number of Residues	5
Details	BINDING SITE FOR RESIDUE CA F 503

Chain	Residue
F	ASP140
F	ASP142
F	ASP144
F	ARG146
F	GLU151

---

site_id	BC2
Number of Residues	5
Details	BINDING SITE FOR RESIDUE ZN E 504

Chain	Residue
E	ASP118
E	ASN150
E	HIS199
E	HIS281
E	FE505

---

site_id	BC3
Number of Residues	4
Details	BINDING SITE FOR RESIDUE FE E 505

Chain	Residue
E	ASP90
E	HIS92
E	ASP118
E	ZN504

---

site_id	BC4
Number of Residues	20
Details	BINDING SITE FOR CHAIN D OF CYCLOSPORIN A

Chain	Residue
A	SER2
A	LEU312
A	TYR341
A	TRP342
A	PRO344
A	TRP352
A	PHE356
B	ASN122
C	ARG55
C	PHE60
C	GLN63
C	GLY72
C	ALA101
C	ASN102
C	GLN111
C	PHE113
C	TRP121
C	LEU122
C	HIS126
C	ARG148

---

site_id	BC5
Number of Residues	21
Details	BINDING SITE FOR CHAIN H OF CYCLOSPORIN A

Chain	Residue
G	TRP121
G	LEU122
G	HIS126
E	LEU312
E	VAL314
E	TYR341
E	TRP342
E	PRO344
E	TRP352
E	PHE356
F	ASN122
F	LEU123
G	ARG55
G	PHE60
G	GLN63
G	GLY72
G	ALA101
G	ASN102
G	ALA103
G	GLN111
G	PHE113

---

Functional Information from PROSITE/UniProt

site_id	PS00018
Number of Residues	13
Details	EF_HAND_1 EF-hand calcium-binding domain. DLDNSGSLSveEF

Chain	Residue	Details
B	ASP30-PHE42
B	ASP62-PHE74
B	ASP99-LEU111
B	ASP140-PHE152

---

site_id	PS00125
Number of Residues	6
Details	SER_THR_PHOSPHATASE Serine/threonine specific protein phosphatases signature. LRGNHE

Chain	Residue	Details
A	LEU147-GLU152

---

site_id	PS00170
Number of Residues	18
Details	CSA_PPIASE_1 Cyclophilin-type peptidyl-prolyl cis-trans isomerase signature. YkgScFHRIIpgFMcQGG

Chain	Residue	Details
C	TYR48-GLY65

---

Functional Information from SwissProt/UniProt

site_id	SWS_FT_FI1
Number of Residues	2
Details	MOD_RES: N-acetylmethionine => ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378, ECO:0007744|PubMed:25944712

Chain	Residue	Details
C	VAL2
B	PHE74
B	LYS141
B	GLY143
B	GLY145
B	ILE147
B	PHE152
F	LEU31
F	ASN33
F	GLY35
F	LEU37
G	VAL2
F	PHE42
F	THR63
F	GLY65
F	GLY67
F	VAL69
F	PHE74
F	LYS141
F	GLY143
F	GLY145
F	ILE147
B	GLY35
F	PHE152
B	LEU37
B	PHE42
B	THR63
B	GLY65
B	GLY67
B	VAL69

---

site_id	SWS_FT_FI2
Number of Residues	2
Details	MOD_RES: N-acetylvaline; partial; in Peptidyl-prolyl cis-trans isomerase A, N-terminally processed => ECO:0000269|PubMed:25489052, ECO:0000269|Ref.12, ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:25944712

Chain	Residue	Details
C	ASN3
F	LEU111
E	HIS199
E	HIS281
G	ASN3
B	GLY104
B	ILE106
B	LEU111
F	MET100
F	LYS102
F	GLY104
F	ILE106

---

site_id	SWS_FT_FI3
Number of Residues	4
Details	MOD_RES: N6-acetyllysine; alternate => ECO:0007744|PubMed:19608861

Chain	Residue	Details
C	VAL29
C	PHE83
G	VAL29
G	PHE83

---

site_id	SWS_FT_FI4
Number of Residues	6
Details	MOD_RES: N6-acetyllysine => ECO:0007744|PubMed:19608861

Chain	Residue	Details
C	GLY45
C	SER77
C	VAL132
G	GLY45
G	SER77
G	VAL132

---

site_id	SWS_FT_FI5
Number of Residues	2
Details	MOD_RES: Phosphoserine => ECO:0007744|PubMed:23186163

Chain	Residue	Details
C	ILE78
G	ILE78

---

site_id	SWS_FT_FI6
Number of Residues	2
Details	MOD_RES: Phosphothreonine => ECO:0007744|PubMed:20068231

Chain	Residue	Details
C	GLY94
G	GLY94

---

site_id	SWS_FT_FI7
Number of Residues	2
Details	MOD_RES: N6-acetyllysine => ECO:0000269|PubMed:20364129, ECO:0000269|PubMed:25678563, ECO:0007744|PubMed:19608861

Chain	Residue	Details
C	HIS126
G	HIS126

---

site_id	SWS_FT_FI8
Number of Residues	2
Details	MOD_RES: N6-acetyllysine => ECO:0000250|UniProtKB:P17742

Chain	Residue	Details
C	GLU134
G	GLU134

---

site_id	SWS_FT_FI9
Number of Residues	2
Details	CARBOHYD: N-linked (GlcNAc...) asparagine => ECO:0000255

Chain	Residue	Details
C	GLY109
G	GLY109

---

site_id	SWS_FT_FI10
Number of Residues	2
Details	CROSSLNK: Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate

Chain	Residue	Details
C	VAL29
G	VAL29

---

site_id	SWS_FT_FI11
Number of Residues	4
Details	CROSSLNK: Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternate => ECO:0007744|PubMed:28112733

Chain	Residue	Details
C	PHE83
G	PHE83

---

Catalytic Information from CSA

site_id	MCSA1
Number of Residues	7
Details	M-CSA 189

Chain	Residue	Details
C	ILE56	electrostatic stabiliser, hydrogen bond donor, steric role
A	HIS281	metal ligand
C	MET61	polar/non-polar interaction, steric role
C	GLY64	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
C	ALA103	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
C	ILE114	polar/non-polar interaction, steric role
C	ASP123	polar/non-polar interaction, steric role
C	VAL127	polar/non-polar interaction, steric role
A	HIS199	metal ligand
A	ARG254	transition state stabiliser

---

site_id	MCSA2
Number of Residues	7
Details	M-CSA 189

Chain	Residue	Details
G	ILE56	electrostatic stabiliser, hydrogen bond donor, steric role
E	HIS281	metal ligand
G	MET61	polar/non-polar interaction, steric role
G	GLY64	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
G	ALA103	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
G	ILE114	polar/non-polar interaction, steric role
G	ASP123	polar/non-polar interaction, steric role
G	VAL127	polar/non-polar interaction, steric role
E	HIS199	metal ligand
E	ARG254	transition state stabiliser

---