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4cf6

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Revision as of 22:05, 5 August 2016

Crystal structure of the complex of the P187S variant of human NAD(P) H:quinone oxidoreductase with Cibacron blue at 2.7 A resolution

Structural highlights

4cf6 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4cet
Activity:	NAD(P)H dehydrogenase (quinone), with EC number 1.6.5.2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[NQO1_HUMAN] The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.

Publication Abstract from PubMed

Human NAD(P)H:quinone oxidoreductase (NQO1) is essential for the antioxidant defence system, stabilization of tumour suppressors (e.g. p53, p33 and p73) and activation of quinone based chemotherapeutics. Overexpression of NQO1 in many solid tumours coupled with its ability to convert quinone-based chemotherapeutics into potent cytotoxic compounds made it a very attractive target for anti-cancer drugs. A naturally occurring single nucleotide polymorphism (transition from C609T) leading to an amino acid exchange (P187S) has been implicated in development of various cancers and poor survival rates following anthracyclin based adjuvant chemotherapy. Despite the importance for cancer prediction and therapy, the exact molecular basis for the loss of function in NQO1 P187S is currently unknown. Therefore we solved the crystal structure of NQO1 P187S. Surprisingly, this structure is virtually identical to NQO1. Employing a combination of NMR spectroscopy and limited proteolysis experiments we demonstrate that the single amino acid exchange destabilizes interactions between the core and C-terminal domain leading to depopulation of the native structure in solution. This collapse of the native structure diminishes cofactor affinity and leads to a less competent FAD binding pocket thus severely compromising the catalytic capacity of the variant protein. Hence our findings provide a rationale for the loss of function in NQO1 P187S due to a frequently occurring single nucleotide polymorphism. This article is protected by copyright. All rights reserved. STRUCTURED DIGITAL ABSTRACT: NQO1 P187S and NQO1 P187S bind by nuclear magnetic resonance (View interaction) NQO1 P187S and NQO1 P187S bind by x-ray crystallography (1, 2) NQO1 and NQO1 bind by molecular sieving (1, 2).

Collapse of the native structure by a single amino acid exchange in human NAD(P)H:quinone oxidoreductase (NQO1).,Lienhart WD, Gudipati V, Uhl MK, Binter A, Pulido S, Saf R, Zangger K, Gruber K, Macheroux P FEBS J. 2014 Aug 20. doi: 10.1111/febs.12975. PMID:25143260^[1]

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

References

↑ Lienhart WD, Gudipati V, Uhl MK, Binter A, Pulido S, Saf R, Zangger K, Gruber K, Macheroux P. Collapse of the native structure by a single amino acid exchange in human NAD(P)H:quinone oxidoreductase (NQO1). FEBS J. 2014 Aug 20. doi: 10.1111/febs.12975. PMID:25143260 doi:http://dx.doi.org/10.1111/febs.12975

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4cf6"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the complex of the P187S variant of human NAD(P) H:quinone oxidoreductase with Cibacron blue at 2.7 A resolution==
 <StructureSection load='4cf6' size='340' side='right' caption='[[4cf6]], [[Resolution|resolution]] 2.69&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4cet|4cet]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/NAD(P)H_dehydrogenase_(quinone) NAD(P)H dehydrogenase (quinone)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.6.5.2 1.6.5.2] </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=4cf6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cf6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4cf6 RCSB], [http://www.ebi.ac.uk/pdbsum/4cf6 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=4cf6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cf6 OCA], [http://pdbe.org/4cf6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cf6 RCSB], [http://www.ebi.ac.uk/pdbsum/4cf6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cf6 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4cf6" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4cf6

From Proteopedia

Revision as of 22:05, 5 August 2016

Crystal structure of the complex of the P187S variant of human NAD(P) H:quinone oxidoreductase with Cibacron blue at 2.7 A resolution

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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