5FUQ

CRYSTAL STRUCTURE OF THE H80R VARIANT OF NQO1 BOUND TO DICOUMAROL

Summary for 5FUQ

• Entry DOI: 10.2210/pdb5fuq/pdb
• Descriptor: NAD(P)H DEHYDROGENASE [QUINONE] 1, FLAVIN-ADENINE DINUCLEOTIDE, BISHYDROXY[2H-1-BENZOPYRAN-2-ONE,1,2-BENZOPYRONE], ... (5 entities in total)
• Functional Keywords: oxidoreductase, nadph-quinone oxidoreductase 1, nqo1, fad, dicoumarol
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P15559
• Total number of polymer chains: 2
• Total formula weight: 64669.48

Authors

Gavira, J.A.,Medina-Carmona, E.,Pey, A.L. (deposition date: 2016-01-29, release date: 2017-02-22, Last modification date: 2024-01-10)

Primary citation

Medina-Carmona, E.,Fuchs, J.E.,Gavira, J.A.,Mesa-Torres, N.,Neira, J.L.,Salido, E.,Palomino-Morales, R.,Burgos, M.,Timson, D.J.,Pey, A.L.
Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution.
Hum.Mol.Genet., 26:3531-3544, 2017

PubMed Abstract: Human proteins are vulnerable towards disease-associated single amino acid replacements affecting protein stability and function. Interestingly, a few studies have shown that consensus amino acids from mammals or vertebrates can enhance protein stability when incorporated into human proteins. Here, we investigate yet unexplored relationships between the high vulnerability of human proteins towards disease-associated inactivation and recent evolutionary site-specific divergence of stabilizing amino acids. Using phylogenetic, structural and experimental analyses, we show that divergence from the consensus amino acids at several sites during mammalian evolution has caused local protein destabilization in two human proteins linked to disease: cancer-associated NQO1 and alanine:glyoxylate aminotransferase, mutated in primary hyperoxaluria type I. We demonstrate that a single consensus mutation (H80R) acts as a disease suppressor on the most common cancer-associated polymorphism in NQO1 (P187S). The H80R mutation reactivates P187S by enhancing FAD binding affinity through local and dynamic stabilization of its binding site. Furthermore, we show how a second suppressor mutation (E247Q) cooperates with H80R in protecting the P187S polymorphism towards inactivation through long-range allosteric communication within the structural ensemble of the protein. Our results support that recent divergence of consensus amino acids may have occurred with neutral effects on many functional and regulatory traits of wild-type human proteins. However, divergence at certain sites may have increased the propensity of some human proteins towards inactivation due to disease-associated mutations and polymorphisms. Consensus mutations also emerge as a potential strategy to identify structural hot-spots in proteins as targets for pharmacological rescue in loss-of-function genetic diseases.

PubMed: 28911204
DOI: 10.1093/hmg/ddx238

Experimental method

X-RAY DIFFRACTION (2.04 Å)