3ntp: Difference between revisions

Revision as of 10:52, 5 August 2016

Human Pin1 complexed with reduced amide inhibitor

Structural highlights

3ntp is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	PE8, RZD
Related:	2itk, 2q5a
Gene:	PIN1 (HUMAN)
Activity:	Peptidylprolyl isomerase, with EC number 5.2.1.8
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PIN1_HUMAN] Essential PPIase that regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Catalyzes pSer/Thr-Pro cis/trans isomerizations. Down-regulates kinase activity of BTK. Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation.^[1] ^[2] ^[3]

Publication Abstract from PubMed

The mechanism of the cell cycle regulatory peptidyl prolyl isomerase (PPIase), Pin1, was investigated using reduced-amide inhibitors designed to mimic the twisted-amide transition state. Inhibitors, R-pSer-Psi[CH(2)N]-Pro-2-(indol-3-yl)ethylamine, 1 [R = fluorenylmethoxycarbonyl (Fmoc)] and 2 (R = Ac), of Pin1 were synthesized and bioassayed. Inhibitor 1 had an IC(50) value of 6.3 muM, which is 4.5-fold better for Pin1 than our comparable ground-state analogue, a cis-amide alkene isostere-containing inhibitor. The change of Fmoc to Ac in 2 improved aqueous solubility for structural determination and resulted in an IC(50) value of 12 muM. The X-ray structure of the complex of 2 bound to Pin1 was determined to 1.76 A resolution. The structure revealed that the reduced amide adopted a conformation similar to the proposed twisted-amide transition state of Pin1, with a trans-pyrrolidine conformation of the prolyl ring. A similar conformation of substrate would be destabilized relative to the planar amide conformation. Three additional reduced amides, with Thr replacing Ser and l- or d-pipecolate (Pip) replacing Pro, were slightly weaker inhibitors of Pin1.

A reduced-amide inhibitor of Pin1 binds in a conformation resembling a twisted-amide transition state.,Xu GG, Zhang Y, Mercedes-Camacho AY, Etzkorn FA Biochemistry. 2011 Nov 8;50(44):9545-50. Epub 2011 Oct 18. PMID:21980916^[4]

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

References

↑ Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005 Jan 21;17(2):215-24. PMID:15664191 doi:10.1016/j.molcel.2004.11.055
↑ Yu L, Mohamed AJ, Vargas L, Berglof A, Finn G, Lu KP, Smith CI. Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1. J Biol Chem. 2006 Jun 30;281(26):18201-7. Epub 2006 Apr 27. PMID:16644721 doi:10.1074/jbc.M603090200
↑ Lee TH, Chen CH, Suizu F, Huang P, Schiene-Fischer C, Daum S, Zhang YJ, Goate A, Chen RH, Zhou XZ, Lu KP. Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Mol Cell. 2011 Apr 22;42(2):147-59. doi: 10.1016/j.molcel.2011.03.005. Epub 2011 , Apr 14. PMID:21497122 doi:10.1016/j.molcel.2011.03.005
↑ Xu GG, Zhang Y, Mercedes-Camacho AY, Etzkorn FA. A reduced-amide inhibitor of Pin1 binds in a conformation resembling a twisted-amide transition state. Biochemistry. 2011 Nov 8;50(44):9545-50. Epub 2011 Oct 18. PMID:21980916 doi:10.1021/bi201055c

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005 Jan 21;17(2):215-24. PMID:15664191 doi:10.1016/j.molcel.2004.11.055

[2] Yu L, Mohamed AJ, Vargas L, Berglof A, Finn G, Lu KP, Smith CI. Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1. J Biol Chem. 2006 Jun 30;281(26):18201-7. Epub 2006 Apr 27. PMID:16644721 doi:10.1074/jbc.M603090200

[3] Lee TH, Chen CH, Suizu F, Huang P, Schiene-Fischer C, Daum S, Zhang YJ, Goate A, Chen RH, Zhou XZ, Lu KP. Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Mol Cell. 2011 Apr 22;42(2):147-59. doi: 10.1016/j.molcel.2011.03.005. Epub 2011 , Apr 14. PMID:21497122 doi:10.1016/j.molcel.2011.03.005

[4] Xu GG, Zhang Y, Mercedes-Camacho AY, Etzkorn FA. A reduced-amide inhibitor of Pin1 binds in a conformation resembling a twisted-amide transition state. Biochemistry. 2011 Nov 8;50(44):9545-50. Epub 2011 Oct 18. PMID:21980916 doi:10.1021/bi201055c

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[2]

[3]

[4]

@@ Line 1: / Line 1: @@
 ==Human Pin1 complexed with reduced amide inhibitor==
 <StructureSection load='3ntp' size='340' side='right' caption='[[3ntp]], [[Resolution|resolution]] 1.76&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3ntp]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NTP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NTP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3ntp]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NTP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NTP FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PE8:3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL'>PE8</scene>, <scene name='pdbligand=RZD:(2R)-2-(ACETYLAMINO)-3-[(2S)-2-{[2-(1H-INDOL-3-YL)ETHYL]CARBAMOYL}PYRROLIDIN-1-YL]PROPYL+DIHYDROGEN+PHOSPHATE'>RZD</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2itk|2itk]], [[2q5a|2q5a]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIN1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIN1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3ntp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ntp OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ntp RCSB], [http://www.ebi.ac.uk/pdbsum/3ntp PDBsum]</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=3ntp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ntp OCA], [http://pdbe.org/3ntp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ntp RCSB], [http://www.ebi.ac.uk/pdbsum/3ntp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ntp ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3ntp" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Peptidyl-prolyl cis-trans isomerase|Peptidyl-prolyl cis-trans isomerase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Peptidylprolyl isomerase]]
 [[Category: Zhang, Y]]

3ntp: Difference between revisions

Revision as of 10:52, 5 August 2016

Human Pin1 complexed with reduced amide inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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