6yi1: Difference between revisions

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== Function ==
== Function ==
[https://www.uniprot.org/uniprot/QPCT_HUMAN 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.<ref>PMID:15063747</ref> <ref>PMID:18486145</ref> <ref>PMID:21288892</ref>  
[https://www.uniprot.org/uniprot/QPCT_HUMAN 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.<ref>PMID:15063747</ref> <ref>PMID:18486145</ref> <ref>PMID:21288892</ref>  
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== Publication Abstract from PubMed ==
Amyloidogenic plaques are hallmarks of Alzheimer's disease (AD) and typically consist of high percentages of modified Abeta peptides bearing N-terminally cyclized glutamate residues. The human zinc(II) enzyme glutaminyl cyclase (QC) was shown in vivo to catalyze the cyclization of N-terminal glutamates of Abeta peptides in a pathophysiological side reaction establishing QC as a druggable target for therapeutic treatment of AD. Here, we report crystallographic snapshots of human QC catalysis acting on the neurohormone neurotensin that delineate the stereochemical course of catalysis and suggest that hydrazides could mimic the transition state of peptide cyclization and deamidation. This hypothesis is validated by a sparse-matrix inhibitor screening campaign that identifies hydrazides as the most potent metal-binding group compared to classic Zn binders. The structural basis of hydrazide inhibition is illuminated by X-ray structure analysis of human QC in complex with a hydrazide-bearing peptide inhibitor and reveals a pentacoordinated Zn complex. Our findings inform novel strategies in the design of potent and highly selective QC inhibitors by employing hydrazides as the metal-binding warhead.
Hydrazides Are Potent Transition-State Analogues for Glutaminyl Cyclase Implicated in the Pathogenesis of Alzheimer's Disease.,Kupski O, Funk LM, Sautner V, Seifert F, Worbs B, Ramsbeck D, Meyer F, Diederichsen U, Buchholz M, Schilling S, Demuth HU, Tittmann K Biochemistry. 2020 Jun 29. doi: 10.1021/acs.biochem.0c00337. PMID:32551535<ref>PMID:32551535</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
==See Also==

Revision as of 10:50, 7 February 2024

Crystal structure of human glutaminyl cyclase in complex with Glu(gamma-hydrazide)-Phe-AlaCrystal structure of human glutaminyl cyclase in complex with Glu(gamma-hydrazide)-Phe-Ala

Structural highlights

6yi1 is a 5 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.92Å
Ligands:, , , , , , , , ,
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]

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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

6yi1, resolution 1.92Å

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OCA
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