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4tot

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Revision as of 10:48, 15 March 2023

Crystal structure of rat cyclophilin D in complex with a potent nonimmunosuppressive inhibitor

Structural highlights

4tot is a 8 chain structure with sequence from Rattus norvegicus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PPIF_RAT PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Involved in regulation of the mitochondrial permeability transition pore (mPTP). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probability of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated. In cooperation with mitochondrial TP53 is involved in activating oxidative stress-induced necrosis. Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels. Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.

Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition.,Fu J, Tjandra M, Becker C, Bednarczyk D, Capparelli M, Elling R, Hanna I, Fujimoto R, Furegati M, Karur S, Kasprzyk T, Knapp M, Leung K, Li X, Lu P, Mergo W, Miault C, Ng S, Parker D, Peng Y, Roggo S, Rivkin A, Simmons RL, Wang M, Wiedmann B, Weiss AH, Xiao L, Xie L, Xu W, Yifru A, Yang S, Zhou B, Sweeney ZK J Med Chem. 2014 Oct 23;57(20):8503-16. doi: 10.1021/jm500862r. Epub 2014 Oct 13. PMID:25310383^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nicolli A, Basso E, Petronilli V, Wenger RM, Bernardi P. Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel. J Biol Chem. 1996 Jan 26;271(4):2185-92. PMID:8567677
↑ Scorrano L, Nicolli A, Basso E, Petronilli V, Bernardi P. Two modes of activation of the permeability transition pore: the role of mitochondrial cyclophilin. Mol Cell Biochem. 1997 Sep;174(1-2):181-4. PMID:9309684
↑ Woodfield K, Ruck A, Brdiczka D, Halestrap AP. Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem J. 1998 Dec 1;336 ( Pt 2):287-90. PMID:9820802
↑ Fu J, Tjandra M, Becker C, Bednarczyk D, Capparelli M, Elling R, Hanna I, Fujimoto R, Furegati M, Karur S, Kasprzyk T, Knapp M, Leung K, Li X, Lu P, Mergo W, Miault C, Ng S, Parker D, Peng Y, Roggo S, Rivkin A, Simmons RL, Wang M, Wiedmann B, Weiss AH, Xiao L, Xie L, Xu W, Yifru A, Yang S, Zhou B, Sweeney ZK. Potent nonimmunosuppressive cyclophilin inhibitors with improved pharmaceutical properties and decreased transporter inhibition. J Med Chem. 2014 Oct 23;57(20):8503-16. doi: 10.1021/jm500862r. Epub 2014 Oct 13. PMID:25310383 doi:http://dx.doi.org/10.1021/jm500862r

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4tot"

Categories: Large Structures | Rattus norvegicus | Synthetic construct | Elling RA | Knapp MS

@@ Line 3: / Line 3: @@
 <StructureSection load='4tot' size='340' side='right'caption='[[4tot]], [[Resolution|resolution]] 2.39&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4tot]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TOT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4TOT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4tot]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TOT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TOT FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=33X:N-METHYL-D-ALANINE'>33X</scene>, <scene name='pdbligand=34E:(3R)-4-[4-(2-METHOXYETHYL)PIPERAZIN-1-YL]-N-METHYL-L-VALINE'>34E</scene>, <scene name='pdbligand=ABA:ALPHA-AMINOBUTYRIC+ACID'>ABA</scene>, <scene name='pdbligand=BMT:4-METHYL-4-[(E)-2-BUTENYL]-4,N-METHYL-THREONINE'>BMT</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=MLE:N-METHYLLEUCINE'>MLE</scene>, <scene name='pdbligand=MVA:N-METHYLVALINE'>MVA</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=33X:N-METHYL-D-ALANINE'>33X</scene>, <scene name='pdbligand=34E:(3R)-4-[4-(2-METHOXYETHYL)PIPERAZIN-1-YL]-N-METHYL-L-VALINE'>34E</scene>, <scene name='pdbligand=ABA:ALPHA-AMINOBUTYRIC+ACID'>ABA</scene>, <scene name='pdbligand=BMT:4-METHYL-4-[(E)-2-BUTENYL]-4,N-METHYL-THREONINE'>BMT</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=MLE:N-METHYLLEUCINE'>MLE</scene>, <scene name='pdbligand=MVA:N-METHYLVALINE'>MVA</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4tot FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tot OCA], [https://pdbe.org/4tot PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tot RCSB], [https://www.ebi.ac.uk/pdbsum/4tot PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tot ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Ppif ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4tot FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tot OCA], [http://pdbe.org/4tot PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4tot RCSB], [http://www.ebi.ac.uk/pdbsum/4tot PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4tot ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/PPIF_RAT PPIF_RAT]] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Involved in regulation of the mitochondrial permeability transition pore (mPTP). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probability of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated. In cooperation with mitochondrial TP53 is involved in activating oxidative stress-induced necrosis. Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels. Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis.<ref>PMID:8567677</ref> <ref>PMID:9309684</ref> <ref>PMID:9820802</ref>
+[https://www.uniprot.org/uniprot/PPIF_RAT PPIF_RAT] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Involved in regulation of the mitochondrial permeability transition pore (mPTP). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probability of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated. In cooperation with mitochondrial TP53 is involved in activating oxidative stress-induced necrosis. Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels. Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis.<ref>PMID:8567677</ref> <ref>PMID:9309684</ref> <ref>PMID:9820802</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 20: @@
 ==See Also==
-*[[Cyclophilin|Cyclophilin]]
+*[[Cyclophilin 3D structures|Cyclophilin 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Buffalo rat]]
 [[Category: Large Structures]]
-[[Category: Peptidylprolyl isomerase]]
+[[Category: Rattus norvegicus]]
-[[Category: Elling, R A]]
+[[Category: Synthetic construct]]
-[[Category: Knapp, M S]]
+[[Category: Elling RA]]
-[[Category: Complex]]
+[[Category: Knapp MS]]
-[[Category: Cyclosporin]]
-[[Category: Inhibitor]]
-[[Category: Isomerase-isomerase inhibitor complex]]

4tot

From Proteopedia

Revision as of 10:48, 15 March 2023

Crystal structure of rat cyclophilin D in complex with a potent nonimmunosuppressive inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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