Unliganded structure of human bisphosphoglycerate mutase reveals side-chain movements induced by ligand binding

Abstract

Erythrocyte-specific bisphosphoglycerate mutase is a trifunctional enzyme which modulates the levels of 2,3-BPG in red blood cells by virtue of its synthase and phosphatase activities. Low levels of erythrocyte 2,3-BPG increases the affinity of haemoglobin for oxygen, thus limiting the release of oxygen into tissues. 2,3-BPG levels in stored blood decline rapidly, due to the phosphatase activity of bisphosphoglycerate mutase which is enhanced by a fall in pH. Here we present the 1.94Å X-ray structure of bisphosphoglycerate mutase, focussing on the dynamic nature of key ligand binding residues and their interaction with the inhibitor, citrate. Residues at the binding pocket are complete. In addition, the movement of key residues in the presence and absence of ligand is described and alternative conformations are explored. We propose the conformation in which the ligand citrate would bind at the substrate binding pocket, with discussion and representations of its orientation. Characterisation of bisphosphoglycerate mutase-citrate interactions will provide a framework for the design of specific inhibitors of the phosphatase activity of this enzyme, which may limit the decline of 2,3-BPG in stored blood.