4KNV

The crystal structure of APO HUMAN HDHD4 FROM SE-MAD

Summary for 4KNV

• Entry DOI: 10.2210/pdb4knv/pdb
• Related: 4KNW
• Descriptor: N-acylneuraminate-9-phosphatase, PHOSPHATE ION, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: n-acetylneuraminate, neu5ac-9-phosphate, carbohydrate metabolism, n-acetylneuraminic acid phosphatase, nanp, hdhd4, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 55132.01

Authors

Klei, H.E. (deposition date: 2013-05-10, release date: 2013-06-26, Last modification date: 2024-11-20)

Primary citation

Kim, S.H.,Constantine, K.L.,Duke, G.J.,Goldfarb, V.,Hunt, J.T.,Johnson, S.,Kish, K.,Klei, H.E.,McDonnell, P.A.,Metzler, W.J.,Mueller, L.,Poss, M.A.,Fairchild, C.R.,Bhide, R.S.
Design, synthesis, functional and structural characterization of an inhibitor of N-acetylneuraminate-9-phosphate phosphatase: Observation of extensive dynamics in an enzyme/inhibitor complex.
Bioorg.Med.Chem.Lett., 23:4107-4111, 2013

PubMed Abstract: The design, synthesis and characterization of a phosphonate inhibitor of N-acetylneuraminate-9-phosphate phosphatase (HDHD4) is described. Compound 3, where the substrate C-9 oxygen was replaced with a nonlabile CH2 group, inhibits HDHD4 with a binding affinity (IC50 11μM) in the range of the native substrate Neu5Ac-9-P (compound 1, Km 47μM). Combined SAR, modeling and NMR studies are consistent with the phosphonate group in inhibitor 3 forming a stable complex with native Mg(2+). In addition to this key interaction, the C-1 carboxylate of the sugar interacts with a cluster of basic residues, K141, R104 and R72. Comparative NMR studies of compounds 3 and 1 with Ca(2+) and Mg(2+) are indicative of a highly dynamic process in the active site for the HDHD4/Mg(2+)/3 complex. Possible explanations for this observation are discussed.

PubMed: 23747226
DOI: 10.1016/j.bmcl.2013.05.052

Experimental method

X-RAY DIFFRACTION (1.993 Å)