2glq
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X-ray structure of human alkaline phosphatase in complex with strontium
OverviewOverview
Strontium is used in the treatment of osteoporosis as a ranelate compound, and in the treatment of painful scattered bone metastases as isotope. At, very high doses and in certain conditions, it can lead to osteomalacia, characterized by impairment of bone mineralization. The osteomalacia, symptoms resemble those of hypophosphatasia, a rare inherited disorder, associated with mutations in the gene encoding for tissue-nonspecific, alkaline phosphatase (TNAP). Human alkaline phosphatases have four metal, binding sites--two for zinc, one for magnesium, and one for calcium, ion--that can be substituted by strontium. Here we present the crystal, structure of strontium-substituted human placental alkaline phosphatase, (PLAP), a related isozyme of TNAP, in which such replacement can have, important physiological implications. The structure shows that strontium, substitutes the calcium ion with concomitant modification of the metal, coordination. The use of the flexible and polarizable force-field TCPEp, (topological and classical polarization effects for proteins) predicts, that calcium or strontium has similar interaction energies at the, calcium-binding site of PLAP. Since calcium helps stabilize a large area, that includes loops 210-228 and 250-297, its substitution by strontium, could affect the stability of this region. Energy calculations suggest, that only at high doses of strontium, comparable to those found for, calcium, can strontium substitute for calcium. Since osteomalacia is, observed after ingestion of high doses of strontium, alkaline phosphatase, is likely to be one of the targets of strontium, and thus this enzyme, might be involved in this disease.
DiseaseDisease
Known disease associated with this structure: Osteoarthritis, susceptibility to OMIM:[608135]
About this StructureAbout this Structure
2GLQ is a Single protein structure of sequence from Homo sapiens with NAG, PO3, ZN, MG and SR as ligands. Active as Alkaline phosphatase, with EC number 3.1.3.1 Full crystallographic information is available from OCA.
ReferenceReference
Structural studies of human alkaline phosphatase in complex with strontium: implication for its secondary effect in bones., Llinas P, Masella M, Stigbrand T, Menez A, Stura EA, Le Du MH, Protein Sci. 2006 Jul;15(7):1691-700. PMID:16815919
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