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2zed

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Revision as of 12:19, 12 October 2017

Crystal structure of the human glutaminyl cyclase mutant S160A at 1.7 angstrom resolution

Structural highlights

2zed is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	2afm, 2zee, 2zef, 2zeg, 2zeh, 2zel, 2zem, 2zen, 2zeo, 2zep
Gene:	QPCT (HUMAN)
Activity:	Glutaminyl-peptide cyclotransferase, with EC number 2.3.2.5
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[QPCT_HUMAN] Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-beta-amyloid. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides.^[1] ^[2] ^[3]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

QCs (glutaminyl cyclases; glutaminyl-peptide cyclotransferases, EC 2.3.2.5) catalyse N-terminal pyroglutamate formation in numerous bioactive peptides and proteins. The enzymes were reported to be involved in several pathological conditions such as amyloidotic disease, osteoporosis, rheumatoid arthritis and melanoma. The crystal structure of human QC revealed an unusual H-bond (hydrogen-bond) network in the active site, formed by several highly conserved residues (Ser(160), Glu(201), Asp(248), Asp(305) and His(319)), within which Glu(201) and Asp(248) were found to bind to substrate. In the present study we combined steady-state enzyme kinetic and X-ray structural analyses of 11 single-mutation human QCs to investigate the roles of the H-bond network in catalysis. Our results showed that disrupting one or both of the central H-bonds, i.e., Glu(201)...Asp(305) and Asp(248)...Asp(305), reduced the steady-state catalysis dramatically. The roles of these two COOH...COOH bonds on catalysis could be partly replaced by COOH...water bonds, but not by COOH...CONH(2) bonds, reminiscent of the low-barrier Asp...Asp H-bond in the active site of pepsin-like aspartic peptidases. Mutations on Asp(305), a residue located at the centre of the H-bond network, raised the K(m) value of the enzyme by 4.4-19-fold, but decreased the k(cat) value by 79-2842-fold, indicating that Asp(305) primarily plays a catalytic role. In addition, results from mutational studies on Ser(160) and His(319) suggest that these two residues might help to stabilize the conformations of Asp(248) and Asp(305) respectively. These data allow us to propose an essential proton transfer between Glu(201), Asp(305) and Asp(248) during the catalysis by animal QCs.

A conserved hydrogen-bond network in the catalytic centre of animal glutaminyl cyclases is critical for catalysis.,Huang KF, Wang YR, Chang EC, Chou TL, Wang AH Biochem J. 2008 Apr 1;411(1):181-90. PMID:18072935^[4]

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

References

↑ Schilling S, Hoffmann T, Manhart S, Hoffmann M, Demuth HU. Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS Lett. 2004 Apr 9;563(1-3):191-6. PMID:15063747 doi:http://dx.doi.org/10.1016/S0014-5793(04)00300-X
↑ Cynis H, Rahfeld JU, Stephan A, Kehlen A, Koch B, Wermann M, Demuth HU, Schilling S. Isolation of an isoenzyme of human glutaminyl cyclase: retention in the Golgi complex suggests involvement in the protein maturation machinery. J Mol Biol. 2008 Jun 20;379(5):966-80. doi: 10.1016/j.jmb.2008.03.078. Epub 2008 , Apr 15. PMID:18486145 doi:http://dx.doi.org/10.1016/j.jmb.2008.03.078
↑ Huang KF, Liaw SS, Huang WL, Chia CY, Lo YC, Chen YL, Wang AH. Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding. J Biol Chem. 2011 Apr 8;286(14):12439-49. Epub 2011 Feb 1. PMID:21288892 doi:10.1074/jbc.M110.208595
↑ Huang KF, Wang YR, Chang EC, Chou TL, Wang AH. A conserved hydrogen-bond network in the catalytic centre of animal glutaminyl cyclases is critical for catalysis. Biochem J. 2008 Apr 1;411(1):181-90. PMID:18072935 doi:http://dx.doi.org/10.1042/BJ20071073

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2zed"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the human glutaminyl cyclase mutant S160A at 1.7 angstrom resolution==
 <StructureSection load='2zed' size='340' side='right' caption='[[2zed]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
@@ Line 7: / Line 8: @@
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">QPCT ([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/Glutaminyl-peptide_cyclotransferase Glutaminyl-peptide cyclotransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.5 2.3.2.5] </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=2zed FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zed OCA], [http://pdbe.org/2zed PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2zed RCSB], [http://www.ebi.ac.uk/pdbsum/2zed 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=2zed FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zed OCA], [http://pdbe.org/2zed PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2zed RCSB], [http://www.ebi.ac.uk/pdbsum/2zed PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2zed ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 30: / Line 31: @@
 </div>
 <div class="pdbe-citations 2zed" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Glutaminyl cyclase|Glutaminyl cyclase]]
 == References ==
 <references/>

2zed

From Proteopedia

Revision as of 12:19, 12 October 2017

Crystal structure of the human glutaminyl cyclase mutant S160A at 1.7 angstrom resolution

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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