5vr8

From Proteopedia

Human UDP-Glucose Dehydrogenase with UDP-Xylose Bound to the Co-enzyme Site

PDB ID 5vr8

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Structural highlights

5vr8 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

UGDH_HUMAN Involved in the biosynthesis of glycosaminoglycans; hyaluronan, chondroitin sulfate, and heparan sulfate.

Publication Abstract from PubMed

Protein structures are dynamic and can explore a large conformational landscape(1,2). Only some of these structural substates are important for protein function (such as ligand binding, catalysis and regulation)(3-5). How evolution shapes the structural ensemble to optimize a specific function is poorly understood(3,4). One of the constraints on the evolution of proteins is the stability of the folded 'native' state. Despite this, 44% of the human proteome contains intrinsically disordered peptide segments greater than 30 residues in length(6), the majority of which have no known function(7-9). Here we show that the entropic force produced by an intrinsically disordered carboxy terminus (ID-tail) shifts the conformational ensemble of human UDP-alpha-D-glucose-6-dehydrogenase (UGDH) towards a substate with a high affinity for an allosteric inhibitor. The function of the ID-tail does not depend on its sequence or chemical composition. Instead, the affinity enhancement can be accurately predicted based on the length of the intrinsically disordered segment, and is consistent with the entropic force generated by an unstructured peptide attached to the protein surface(10-13). Our data show that the unfolded state of the ID-tail rectifies the dynamics and structure of UGDH to favour inhibitor binding. Because this entropic rectifier does not have any sequence or structural constraints, it is an easily acquired adaptation. This model implies that evolution selects for disordered segments to tune the energy landscape of proteins, which may explain the persistence of intrinsic disorder in the proteome.

The entropic force generated by intrinsically disordered segments tunes protein function.,Keul ND, Oruganty K, Schaper Bergman ET, Beattie NR, McDonald WE, Kadirvelraj R, Gross ML, Phillips RS, Harvey SC, Wood ZA Nature. 2018 Nov;563(7732):584-588. doi: 10.1038/s41586-018-0699-5. Epub 2018 Nov, 12. PMID:30420606^[1]

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

References

↑ Keul ND, Oruganty K, Schaper Bergman ET, Beattie NR, McDonald WE, Kadirvelraj R, Gross ML, Phillips RS, Harvey SC, Wood ZA. The entropic force generated by intrinsically disordered segments tunes protein function. Nature. 2018 Nov;563(7732):584-588. doi: 10.1038/s41586-018-0699-5. Epub 2018 Nov, 12. PMID:30420606 doi:http://dx.doi.org/10.1038/s41586-018-0699-5