4dm9: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==The Crystal Structure of Ubiquitin Carboxy-terminal hydrolase L1 (UCHL1) bound to a tripeptide fluoromethyl ketone Z-VAE(OMe)-FMK== | |||
<StructureSection load='4dm9' size='340' side='right' caption='[[4dm9]], [[Resolution|resolution]] 2.35Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4dm9]] is a 4 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=4DM9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DM9 FirstGlance]. <br> | |||
</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CF0:FLUOROMETHANE'>CF0</scene>, <scene name='pdbligand=GME:5-O-METHYL-GLUTAMIC+ACID'>GME</scene>, <scene name='pdbligand=PHQ:BENZYL+CHLOROCARBONATE'>PHQ</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2etl|2etl]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UCHL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4dm9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dm9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dm9 RCSB], [http://www.ebi.ac.uk/pdbsum/4dm9 PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/UCHL1_HUMAN UCHL1_HUMAN]] Defects in UCHL1 are the cause of Parkinson disease type 5 (PARK5) [MIM:[http://omim.org/entry/613643 613643]]; also known as Parkinson disease autosomal dominant 5. PARK5 is a complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia.<ref>PMID:12408865</ref> <ref>PMID:9774100</ref> <ref>PMID:12705903</ref> <ref>PMID:16450370</ref> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/UCHL1_HUMAN UCHL1_HUMAN]] Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. Also binds to free monoubiquitin and may prevent its degradation in lysosomes. The homodimer may have ATP-independent ubiquitin ligase activity.<ref>PMID:9790970</ref> <ref>PMID:12408865</ref> <ref>PMID:18411255</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
UCHL1 is a 223 amino acid member of the UCH family of deubiquitinating enzymes (DUBs), found abundantly and exclusively expressed in neurons and the testis in normal tissues. Two naturally occurring variants of UCHL1 are directly involved in Parkinson's disease (PD). Not only has UCHL1 been linked to PD, but it has oncogenic properties, having been found abnormally expressed in lung, pancreatic, and colorectal cancers. Although inhibitors of UCHL1 have been described previously the co-crystal structure of the enzyme bound to any inhibitor has not been reported. Herein, we report the X-ray structure of UCHL1 co-crystallized with a peptide-based fluoromethylketone inhibitor, Z-VAE(OMe)-FMK (VAEFMK) at 2.35A resolution. The co-crystal structure reveals that the inhibitor binds in the active-site cleft, irreversibly modifying the active-site cysteine; however, the catalytic histidine is still misaligned as seen in the native structure, suggesting that the inhibitor binds to an inactive form of the enzyme. Our structure also reveals that the inhibitor approaches the active-site cleft from the opposite side of the crossover loop as compared to the direction of approach of ubiquitin's C-terminal tail, thereby occupying the P1' (leaving group) site, a binding site perhaps used by the unknown C-terminal extension of ubiquitin in the actual in vivo substrate(s) of UCHL1. This structure provides a view of molecular contacts at the active-site cleft between the inhibitor and the enzyme as well as furnishing structural information needed to facilitate further design of inhibitors targeted to UCHL1 with high selectivity and potency. | |||
The co-crystal structure of ubiquitin carboxy-terminal hydrolase L1 (UCHL1) with a tripeptide fluoromethyl ketone (Z-VAE(OMe)-FMK).,Davies CW, Chaney J, Korbel G, Ringe D, Petsko GA, Ploegh H, Das C Bioorg Med Chem Lett. 2012 Jun 15;22(12):3900-4. Epub 2012 May 4. PMID:22617491<ref>PMID:22617491</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
[[ | *[[Thioesterase|Thioesterase]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Chaney, J | [[Category: Chaney, J]] | ||
[[Category: Das, C | [[Category: Das, C]] | ||
[[Category: Davies, C W | [[Category: Davies, C W]] | ||
[[Category: Korbel, G | [[Category: Korbel, G]] | ||
[[Category: Petsko, G A | [[Category: Petsko, G A]] | ||
[[Category: Ploegh, H | [[Category: Ploegh, H]] | ||
[[Category: Ringe, D | [[Category: Ringe, D]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Ligase]] | [[Category: Ligase]] | ||
[[Category: Ligase-inhibitor complex]] | [[Category: Ligase-inhibitor complex]] | ||
[[Category: Ubiquitin hydrolase]] | [[Category: Ubiquitin hydrolase]] | ||
Revision as of 11:52, 21 December 2014
The Crystal Structure of Ubiquitin Carboxy-terminal hydrolase L1 (UCHL1) bound to a tripeptide fluoromethyl ketone Z-VAE(OMe)-FMKThe Crystal Structure of Ubiquitin Carboxy-terminal hydrolase L1 (UCHL1) bound to a tripeptide fluoromethyl ketone Z-VAE(OMe)-FMK
Structural highlights
Disease[UCHL1_HUMAN] Defects in UCHL1 are the cause of Parkinson disease type 5 (PARK5) [MIM:613643]; also known as Parkinson disease autosomal dominant 5. PARK5 is a complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia.[1] [2] [3] [4] Function[UCHL1_HUMAN] Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. Also binds to free monoubiquitin and may prevent its degradation in lysosomes. The homodimer may have ATP-independent ubiquitin ligase activity.[5] [6] [7] Publication Abstract from PubMedUCHL1 is a 223 amino acid member of the UCH family of deubiquitinating enzymes (DUBs), found abundantly and exclusively expressed in neurons and the testis in normal tissues. Two naturally occurring variants of UCHL1 are directly involved in Parkinson's disease (PD). Not only has UCHL1 been linked to PD, but it has oncogenic properties, having been found abnormally expressed in lung, pancreatic, and colorectal cancers. Although inhibitors of UCHL1 have been described previously the co-crystal structure of the enzyme bound to any inhibitor has not been reported. Herein, we report the X-ray structure of UCHL1 co-crystallized with a peptide-based fluoromethylketone inhibitor, Z-VAE(OMe)-FMK (VAEFMK) at 2.35A resolution. The co-crystal structure reveals that the inhibitor binds in the active-site cleft, irreversibly modifying the active-site cysteine; however, the catalytic histidine is still misaligned as seen in the native structure, suggesting that the inhibitor binds to an inactive form of the enzyme. Our structure also reveals that the inhibitor approaches the active-site cleft from the opposite side of the crossover loop as compared to the direction of approach of ubiquitin's C-terminal tail, thereby occupying the P1' (leaving group) site, a binding site perhaps used by the unknown C-terminal extension of ubiquitin in the actual in vivo substrate(s) of UCHL1. This structure provides a view of molecular contacts at the active-site cleft between the inhibitor and the enzyme as well as furnishing structural information needed to facilitate further design of inhibitors targeted to UCHL1 with high selectivity and potency. The co-crystal structure of ubiquitin carboxy-terminal hydrolase L1 (UCHL1) with a tripeptide fluoromethyl ketone (Z-VAE(OMe)-FMK).,Davies CW, Chaney J, Korbel G, Ringe D, Petsko GA, Ploegh H, Das C Bioorg Med Chem Lett. 2012 Jun 15;22(12):3900-4. Epub 2012 May 4. PMID:22617491[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||