1JUJ

Human Thymidylate Synthase Bound to dUMP and LY231514, a Pyrrolo(2,3-d)pyrimidine-based Antifolate

Summary for 1JUJ

• Entry DOI: 10.2210/pdb1juj/pdb
• Related: 1JTQ 1JTU 1JU6 1JUT
• Descriptor: THYMIDYLATE SYNTHASE, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, 2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC ACID (3 entities in total)
• Functional Keywords: cancer, dtmp synthesis, antifolate, drug resistance, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 145881.81

Authors

Sayre, P.H.,Finer-Moore, J.S.,Fritz, T.A.,Biermann, D.,Gates, S.B.,MacKellar, W.C.,Patel, V.F.,Stroud, R.M. (deposition date: 2001-08-24, release date: 2001-09-19, Last modification date: 2024-10-30)

Primary citation

Sayre, P.H.,Finer-Moore, J.S.,Fritz, T.A.,Biermann, D.,Gates, S.B.,MacKellar, W.C.,Patel, V.F.,Stroud, R.M.
Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases.
J.Mol.Biol., 313:813-829, 2001

PubMed Abstract: Crystal structures of four pyrrolo(2,3-d)pyrimidine-based antifolate compounds, developed as inhibitors of thymidylate synthase (TS) in a strategy to circumvent drug-resistance, have been determined in complexes with their in vivo target, human thymidylate synthase, and with the structurally best-characterized Escherichia coli enzyme, to resolutions of 2.2-3.0 A. The 2.9 A crystal structure of a complex of human TS with one of the inhibitors, the multi-targeted antifolate LY231514, demonstrates that this compound induces a "closed" enzyme conformation and leads to formation of a covalent bond between enzyme and substrate. This structure is one of the first liganded human TS structures, and its solution was aided by mutation to facilitate crystallization. Structures of three other pyrrolo(2,3-d)pyrimidine-based antifolates in complex with Escherichia coli TS confirm the orientation of this class of inhibitors in the active site. Specific interactions between the polyglutamyl moiety and a positively charged groove on the enzyme surface explain the marked increase in affinity of the pyrrolo(2,3-d)pyrimidine inhibitors once they are polyglutamylated, as mediated in vivo by the cellular enzyme folyl polyglutamate synthetase.

PubMed: 11697906
DOI: 10.1006/jmbi.2001.5074

Experimental method

X-RAY DIFFRACTION (3 Å)