5T9U

Discovery of a Potent Cyclophilin Inhibitor (Compound 3) based on Structural Simplification of Sanglifehrin A

Functional Information from GO Data

Chain	GOid	namespace	contents
A	0000413	biological_process	protein peptidyl-prolyl isomerization
A	0001933	biological_process	negative regulation of protein phosphorylation
A	0001934	biological_process	positive regulation of protein phosphorylation
A	0003723	molecular_function	RNA binding
A	0003755	molecular_function	peptidyl-prolyl cis-trans isomerase activity
A	0005178	molecular_function	integrin binding
A	0005515	molecular_function	protein binding
A	0005576	cellular_component	extracellular region
A	0005615	cellular_component	extracellular space
A	0005634	cellular_component	nucleus
A	0005737	cellular_component	cytoplasm
A	0005829	cellular_component	cytosol
A	0005925	cellular_component	focal adhesion
A	0006457	biological_process	protein folding
A	0006469	biological_process	negative regulation of protein kinase activity
A	0006915	biological_process	apoptotic process
A	0016018	molecular_function	cyclosporin A binding
A	0016020	cellular_component	membrane
A	0019076	biological_process	viral release from host cell
A	0030168	biological_process	platelet activation
A	0030182	biological_process	neuron differentiation
A	0030593	biological_process	neutrophil chemotaxis
A	0030595	biological_process	leukocyte chemotaxis
A	0031982	cellular_component	vesicle
A	0032148	biological_process	activation of protein kinase B activity
A	0032873	biological_process	negative regulation of stress-activated MAPK cascade
A	0032991	cellular_component	protein-containing complex
A	0034389	biological_process	lipid droplet organization
A	0034599	biological_process	cellular response to oxidative stress
A	0034774	cellular_component	secretory granule lumen
A	0035307	biological_process	obsolete positive regulation of protein dephosphorylation
A	0042118	biological_process	endothelial cell activation
A	0043410	biological_process	positive regulation of MAPK cascade
A	0045069	biological_process	regulation of viral genome replication
A	0045070	biological_process	positive regulation of viral genome replication
A	0046790	molecular_function	virion binding
A	0050714	biological_process	positive regulation of protein secretion
A	0051082	molecular_function	unfolded protein binding
A	0051092	biological_process	positive regulation of NF-kappaB transcription factor activity
A	0060352	biological_process	cell adhesion molecule production
A	0061944	biological_process	negative regulation of protein K48-linked ubiquitination
A	0070062	cellular_component	extracellular exosome
A	0070527	biological_process	platelet aggregation
A	1902176	biological_process	negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
A	1903901	biological_process	negative regulation of viral life cycle
A	1904399	molecular_function	heparan sulfate binding
A	1904813	cellular_component	ficolin-1-rich granule lumen
A	2001233	biological_process	regulation of apoptotic signaling pathway
B	0000413	biological_process	protein peptidyl-prolyl isomerization
B	0001933	biological_process	negative regulation of protein phosphorylation
B	0001934	biological_process	positive regulation of protein phosphorylation
B	0003723	molecular_function	RNA binding
B	0003755	molecular_function	peptidyl-prolyl cis-trans isomerase activity
B	0005178	molecular_function	integrin binding
B	0005515	molecular_function	protein binding
B	0005576	cellular_component	extracellular region
B	0005615	cellular_component	extracellular space
B	0005634	cellular_component	nucleus
B	0005737	cellular_component	cytoplasm
B	0005829	cellular_component	cytosol
B	0005925	cellular_component	focal adhesion
B	0006457	biological_process	protein folding
B	0006469	biological_process	negative regulation of protein kinase activity
B	0006915	biological_process	apoptotic process
B	0016018	molecular_function	cyclosporin A binding
B	0016020	cellular_component	membrane
B	0019076	biological_process	viral release from host cell
B	0030168	biological_process	platelet activation
B	0030182	biological_process	neuron differentiation
B	0030593	biological_process	neutrophil chemotaxis
B	0030595	biological_process	leukocyte chemotaxis
B	0031982	cellular_component	vesicle
B	0032148	biological_process	activation of protein kinase B activity
B	0032873	biological_process	negative regulation of stress-activated MAPK cascade
B	0032991	cellular_component	protein-containing complex
B	0034389	biological_process	lipid droplet organization
B	0034599	biological_process	cellular response to oxidative stress
B	0034774	cellular_component	secretory granule lumen
B	0035307	biological_process	obsolete positive regulation of protein dephosphorylation
B	0042118	biological_process	endothelial cell activation
B	0043410	biological_process	positive regulation of MAPK cascade
B	0045069	biological_process	regulation of viral genome replication
B	0045070	biological_process	positive regulation of viral genome replication
B	0046790	molecular_function	virion binding
B	0050714	biological_process	positive regulation of protein secretion
B	0051082	molecular_function	unfolded protein binding
B	0051092	biological_process	positive regulation of NF-kappaB transcription factor activity
B	0060352	biological_process	cell adhesion molecule production
B	0061944	biological_process	negative regulation of protein K48-linked ubiquitination
B	0070062	cellular_component	extracellular exosome
B	0070527	biological_process	platelet aggregation
B	1902176	biological_process	negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
B	1903901	biological_process	negative regulation of viral life cycle
B	1904399	molecular_function	heparan sulfate binding
B	1904813	cellular_component	ficolin-1-rich granule lumen
B	2001233	biological_process	regulation of apoptotic signaling pathway
C	0000413	biological_process	protein peptidyl-prolyl isomerization
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	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	obsolete positive regulation of protein dephosphorylation
C	0042118	biological_process	endothelial cell activation
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
D	0000413	biological_process	protein peptidyl-prolyl isomerization
D	0001933	biological_process	negative regulation of protein phosphorylation
D	0001934	biological_process	positive regulation of protein phosphorylation
D	0003723	molecular_function	RNA binding
D	0003755	molecular_function	peptidyl-prolyl cis-trans isomerase activity
D	0005178	molecular_function	integrin binding
D	0005515	molecular_function	protein binding
D	0005576	cellular_component	extracellular region
D	0005615	cellular_component	extracellular space
D	0005634	cellular_component	nucleus
D	0005737	cellular_component	cytoplasm
D	0005829	cellular_component	cytosol
D	0005925	cellular_component	focal adhesion
D	0006457	biological_process	protein folding
D	0006469	biological_process	negative regulation of protein kinase activity
D	0006915	biological_process	apoptotic process
D	0016018	molecular_function	cyclosporin A binding
D	0016020	cellular_component	membrane
D	0019076	biological_process	viral release from host cell
D	0030168	biological_process	platelet activation
D	0030182	biological_process	neuron differentiation
D	0030593	biological_process	neutrophil chemotaxis
D	0030595	biological_process	leukocyte chemotaxis
D	0031982	cellular_component	vesicle
D	0032148	biological_process	activation of protein kinase B activity
D	0032873	biological_process	negative regulation of stress-activated MAPK cascade
D	0032991	cellular_component	protein-containing complex
D	0034389	biological_process	lipid droplet organization
D	0034599	biological_process	cellular response to oxidative stress
D	0034774	cellular_component	secretory granule lumen
D	0035307	biological_process	obsolete positive regulation of protein dephosphorylation
D	0042118	biological_process	endothelial cell activation
D	0043410	biological_process	positive regulation of MAPK cascade
D	0045069	biological_process	regulation of viral genome replication
D	0045070	biological_process	positive regulation of viral genome replication
D	0046790	molecular_function	virion binding
D	0050714	biological_process	positive regulation of protein secretion
D	0051082	molecular_function	unfolded protein binding
D	0051092	biological_process	positive regulation of NF-kappaB transcription factor activity
D	0060352	biological_process	cell adhesion molecule production
D	0061944	biological_process	negative regulation of protein K48-linked ubiquitination
D	0070062	cellular_component	extracellular exosome
D	0070527	biological_process	platelet aggregation
D	1902176	biological_process	negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
D	1903901	biological_process	negative regulation of viral life cycle
D	1904399	molecular_function	heparan sulfate binding
D	1904813	cellular_component	ficolin-1-rich granule lumen
D	2001233	biological_process	regulation of apoptotic signaling pathway

Functional Information from PDB Data

site_id	AC1
Number of Residues	16
Details	binding site for (3S,6S,9R,10R,11S,12S,13E,15E,21S)-3-[(3-hydroxyphenyl)methyl]-10,12-dimethoxy-9,11-dimethyl-6-(propan-2-yl)-19-oxa-1,4,7,25-tetraazabicyclo[19.3.1]pentacosa-13,15-diene-2,5,8,20-tetrone chain A

Chain	Residue
A	ARG55
A	LEU122
A	HIS126
A	HOH401
A	HOH408
B	TRP121
B	LYS125
B	7HG300
A	MET61
A	GLN63
A	THR73
A	ALA101
A	ASN102
A	ALA103
A	GLN111
A	PHE113

---

site_id	AC2
Number of Residues	17
Details	binding site for (3S,6S,9R,10R,11S,12S,13E,15E,21S)-3-[(3-hydroxyphenyl)methyl]-10,12-dimethoxy-9,11-dimethyl-6-(propan-2-yl)-19-oxa-1,4,7,25-tetraazabicyclo[19.3.1]pentacosa-13,15-diene-2,5,8,20-tetrone chain B

Chain	Residue
A	TRP121
A	7HG300
B	ARG55
B	MET61
B	GLN63
B	GLY72
B	THR73
B	ALA101
B	ASN102
B	ALA103
B	GLN111
B	PHE113
B	LEU122
B	HIS126
B	HOH404
B	HOH412
B	HOH431

---

site_id	AC3
Number of Residues	14
Details	binding site for (3S,6S,9R,10R,11S,12S,13E,15E,21S)-3-[(3-hydroxyphenyl)methyl]-10,12-dimethoxy-9,11-dimethyl-6-(propan-2-yl)-19-oxa-1,4,7,25-tetraazabicyclo[19.3.1]pentacosa-13,15-diene-2,5,8,20-tetrone chain C

Chain	Residue
C	ARG55
C	MET61
C	GLN63
C	ALA101
C	ASN102
C	ALA103
C	GLN111
C	PHE113
C	LEU122
C	HIS126
C	HOH413
D	TRP121
D	7HG300
D	HOH467

---

site_id	AC4
Number of Residues	16
Details	binding site for (3S,6S,9R,10R,11S,12S,13E,15E,21S)-3-[(3-hydroxyphenyl)methyl]-10,12-dimethoxy-9,11-dimethyl-6-(propan-2-yl)-19-oxa-1,4,7,25-tetraazabicyclo[19.3.1]pentacosa-13,15-diene-2,5,8,20-tetrone chain D

Chain	Residue
C	TRP121
C	7HG300
D	ARG55
D	MET61
D	GLN63
D	GLY72
D	THR73
D	ALA101
D	ASN102
D	ALA103
D	GLN111
D	PHE113
D	LEU122
D	HIS126
D	HOH412
D	HOH423

---

Functional Information from PROSITE/UniProt

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

Chain	Residue	Details
A	TYR48-GLY65

---

Functional Information from SwissProt/UniProt

site_id	SWS_FT_FI1
Number of Residues	4
Details	MOD_RES: N-acetylmethionine => ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378, ECO:0007744|PubMed:25944712

Chain	Residue	Details
A	MET1
B	MET1
C	MET1
D	MET1

---

site_id	SWS_FT_FI2
Number of Residues	4
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
A	VAL2
B	VAL2
C	VAL2
D	VAL2

---

site_id	SWS_FT_FI3
Number of Residues	8
Details	MOD_RES: N6-acetyllysine; alternate => ECO:0007744|PubMed:19608861

Chain	Residue	Details
A	LYS28
A	LYS82
B	LYS28
B	LYS82
C	LYS28
C	LYS82
D	LYS28
D	LYS82

---

site_id	SWS_FT_FI4
Number of Residues	12
Details	MOD_RES: N6-acetyllysine => ECO:0007744|PubMed:19608861

Chain	Residue	Details
A	LYS44
D	LYS44
D	LYS76
D	LYS131
A	LYS76
A	LYS131
B	LYS44
B	LYS76
B	LYS131
C	LYS44
C	LYS76
C	LYS131

---

site_id	SWS_FT_FI5
Number of Residues	4
Details	MOD_RES: Phosphoserine => ECO:0007744|PubMed:23186163

Chain	Residue	Details
A	SER77
B	SER77
C	SER77
D	SER77

---

site_id	SWS_FT_FI6
Number of Residues	4
Details	MOD_RES: Phosphothreonine => ECO:0007744|PubMed:20068231

Chain	Residue	Details
A	THR93
B	THR93
C	THR93
D	THR93

---

site_id	SWS_FT_FI7
Number of Residues	4
Details	MOD_RES: N6-acetyllysine => ECO:0000269|PubMed:20364129, ECO:0000269|PubMed:25678563, ECO:0007744|PubMed:19608861

Chain	Residue	Details
A	LYS125
B	LYS125
C	LYS125
D	LYS125

---

site_id	SWS_FT_FI8
Number of Residues	4
Details	MOD_RES: N6-acetyllysine => ECO:0000250|UniProtKB:P17742

Chain	Residue	Details
A	LYS133
B	LYS133
C	LYS133
D	LYS133

---

site_id	SWS_FT_FI9
Number of Residues	4
Details	CARBOHYD: N-linked (GlcNAc...) asparagine => ECO:0000255

Chain	Residue	Details
A	ASN108
B	ASN108
C	ASN108
D	ASN108

---

site_id	SWS_FT_FI10
Number of Residues	4
Details	CROSSLNK: Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate

Chain	Residue	Details
A	LYS28
B	LYS28
C	LYS28
D	LYS28

---

site_id	SWS_FT_FI11
Number of Residues	8
Details	CROSSLNK: Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternate => ECO:0007744|PubMed:28112733

Chain	Residue	Details
A	LYS82
B	LYS82
C	LYS82
D	LYS82

---

Catalytic Information from CSA

site_id	MCSA1
Number of Residues	7
Details	M-CSA 189

Chain	Residue	Details
A	ARG55	electrostatic stabiliser, hydrogen bond donor, steric role
A	PHE60	polar/non-polar interaction, steric role
A	GLN63	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
A	ASN102	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
A	PHE113	polar/non-polar interaction, steric role
A	LEU122	polar/non-polar interaction, steric role
A	HIS126	polar/non-polar interaction, steric role

---

site_id	MCSA2
Number of Residues	7
Details	M-CSA 189

Chain	Residue	Details
B	ARG55	electrostatic stabiliser, hydrogen bond donor, steric role
B	PHE60	polar/non-polar interaction, steric role
B	GLN63	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
B	ASN102	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
B	PHE113	polar/non-polar interaction, steric role
B	LEU122	polar/non-polar interaction, steric role
B	HIS126	polar/non-polar interaction, steric role

---

site_id	MCSA3
Number of Residues	7
Details	M-CSA 189

Chain	Residue	Details
C	ARG55	electrostatic stabiliser, hydrogen bond donor, steric role
C	PHE60	polar/non-polar interaction, steric role
C	GLN63	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
C	ASN102	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
C	PHE113	polar/non-polar interaction, steric role
C	LEU122	polar/non-polar interaction, steric role
C	HIS126	polar/non-polar interaction, steric role

---

site_id	MCSA4
Number of Residues	7
Details	M-CSA 189

Chain	Residue	Details
D	ARG55	electrostatic stabiliser, hydrogen bond donor, steric role
D	PHE60	polar/non-polar interaction, steric role
D	GLN63	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
D	ASN102	electrostatic stabiliser, hydrogen bond acceptor, hydrogen bond donor
D	PHE113	polar/non-polar interaction, steric role
D	LEU122	polar/non-polar interaction, steric role
D	HIS126	polar/non-polar interaction, steric role

---