1RR6

Structure of human purine nucleoside phosphorylase in complex with Immucillin-H and phosphate

Summary for 1RR6

• Entry DOI: 10.2210/pdb1rr6/pdb
• Related: 1RSZ 1RT9
• Descriptor: Purine nucleoside phosphorylase, PHOSPHATE ION, 1,4-DIDEOXY-4-AZA-1-(S)-(9-DEAZAHYPOXANTHIN-9-YL)-D-RIBITOL, ... (4 entities in total)
• Functional Keywords: pnp, transition state analogue, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton (By similarity): P00491
• Total number of polymer chains: 1
• Total formula weight: 32736.04

Authors

Shi, W.,Lewandowicz, A.,Tyler, P.C.,Furneaux, R.H.,Almo, S.C.,Schramm, V.L. (deposition date: 2003-12-08, release date: 2005-02-22, Last modification date: 2023-09-20)

Primary citation

Shi, W.,Ting, L.M.,Kicska, G.A.,Lewandowicz, A.,Tyler, P.C.,Evans, G.B.,Furneaux, R.H.,Kim, K.,Almo, S.C.,Schramm, V.L.
Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function.
J.Biol.Chem., 279:18103-18106, 2004

PubMed Abstract: Purine nucleoside phosphorylase from Plasmodium falciparum (PfPNP) is an anti-malarial target based on the activity of Immucillins. The crystal structure of PfPNP.Immucillin-H (ImmH).SO(4) reveals a homohexamer with ImmH and SO(4) bound at each catalytic site. A solvent-filled cavity close to the 5'-hydroxyl group of ImmH suggested that PfPNP can accept additional functional groups at the 5'-carbon. Assays established 5'-methylthioinosine (MTI) as a substrate for PfPNP. MTI is not found in human metabolism. These properties of PfPNP suggest unusual purine pathways in P. falciparum and provide structural and mechanistic foundations for the design of malaria-specific transition state analogue inhibitors. 5'-Methylthio-Immucillin-H (MT-ImmH) was designed to resemble the transition state of PfPNP and binds to PfPNP and human-PNP with K(d) values of 2.7 and 303 nm, respectively, to give a discrimination factor of 112. MT-ImmH is the first inhibitor that favors PfPNP inhibition. The structure of PfPNP.MT-ImmH.SO(4) shows that the hydrophobic methylthio group inserts into a hydrophobic region adjacent to the more hydrophilic 5'-hydroxyl binding site of ImmH. The catalytic features of PfPNP indicate a dual cellular function in purine salvage and polyamine metabolism. Combined metabolic functions in a single enzyme strengthen the rationale for targeting PfPNP in anti-malarial action.

PubMed: 14982926
DOI: 10.1074/jbc.C400068200

Experimental method

X-RAY DIFFRACTION (2.5 Å)