PDBsum entry 1cb0

Transferase

PDB id: 1cb0

Contents

Protein chain

268 a.a. *

Ligands

ADE

Waters ×173

* Residue conservation analysis

References listed in PDB file

Key reference

• Title: The structure of human 5'-Deoxy-5'-Methylthioadenosine phosphorylase at 1.7 a resolution provides insights into substrate binding and catalysis.
• Authors: T.C.Appleby, M.D.Erion, S.E.Ealick.
• Ref.: Structure, 1999, 7, 629-641. [DOI no: 10.1016/S0969-2126(99)80084-7]
• PubMed id: 10404592

Abstract

BACKGROUND: 5'-Deoxy-5'-methylthioadenosine phosphorylase (MTAP) catalyzes the reversible phosphorolysis of 5'-deoxy-5'-methylthioadenosine (MTA) to adenine and 5-methylthio-D-ribose-1-phosphate. MTA is a by-product of polyamine biosynthesis, which is essential for cell growth and proliferation. This salvage reaction is the principle source of free adenine in human cells. Because of its importance in coupling the purine salvage pathway to polyamine biosynthesis MTAP is a potential chemotherapeutic target. RESULTS: We have determined the crystal structure of MTAP at 1.7 A resolution using multiwavelength anomalous diffraction phasing techniques. MTAP is a trimer comprised of three identical subunits. Each subunit consists of a single alpha/beta domain containing a central eight-stranded mixed beta sheet, a smaller five-stranded mixed beta sheet and six alpha helices. The native structure revealed the presence of an adenine molecule in the purine-binding site. The structure of MTAP with methylthioadenosine and sulfate ion soaked into the active site was also determined using diffraction data to 1.7 A resolution. CONCLUSIONS: The overall quaternary structure and subunit topology of MTAP are similar to mammalian purine nucleoside phosphorylase (PNP). The structures of the MTAP-ligand complexes provide a map of the active site and suggest possible roles for specific residues in substrate binding and catalysis. Residues accounting for the differences in substrate specificity between MTAP and PNP are also identified. Detailed information about the structure and chemical nature of the MTAP active site will aid in the rational design of inhibitors of this potential chemotherapeutic target. The MTAP structure represents the first structure of a mammalian PNP that is specific for 6-aminopurines.

Figure 3.
Figure 3. Stereoview of the MTAP trimer. The trimer is viewed down the molecular/crystallographic threefold axis. Each subunit is shown in a different color, with MTA and sulfate modeled in red in each of the three active sites. Broken lines indicate residues 225–229, which are missing in the final model. (The figure was produced using the program MOLSCRIPT [41].)

The above figure is reprinted by permission from Cell Press: Structure (1999, 7, 629-641) copyright 1999.