1nn5: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:1nn5.gif|left|200px]] | [[Image:1nn5.gif|left|200px]] | ||
<!-- | |||
The line below this paragraph, containing "STRUCTURE_1nn5", creates the "Structure Box" on the page. | |||
You may change the PDB parameter (which sets the PDB file loaded into the applet) | |||
or the SCENE parameter (which sets the initial scene displayed when the page is loaded), | |||
or leave the SCENE parameter empty for the default display. | |||
| | --> | ||
| | {{STRUCTURE_1nn5| PDB=1nn5 | SCENE= }} | ||
}} | |||
'''Crystal structure of human thymidylate kinase with d4TMP + AppNHp''' | '''Crystal structure of human thymidylate kinase with d4TMP + AppNHp''' | ||
| Line 25: | Line 22: | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: | [[Category: DTMP kinase]] | ||
[[Category: Konrad, M.]] | [[Category: Konrad, M.]] | ||
[[Category: Lavie, A.]] | [[Category: Lavie, A.]] | ||
| Line 33: | Line 30: | ||
[[Category: Segura-Pena, D.]] | [[Category: Segura-Pena, D.]] | ||
[[Category: Veit, T.]] | [[Category: Veit, T.]] | ||
[[Category: | [[Category: D4tmp]] | ||
[[Category: | [[Category: P-loop]] | ||
[[Category: | [[Category: Thymidylate kinase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:44:10 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 02:44, 3 May 2008
Crystal structure of human thymidylate kinase with d4TMP + AppNHp
OverviewOverview
Nucleoside analogue prodrugs are dependent on efficient intracellular stepwise phosphorylation to their triphosphate form to become therapeutically active. In many cases it is this activation pathway that largely determines the efficacy of the drug. To gain further understanding of the determinants for efficient conversion by the enzyme thymidylate kinase (TMPK) of clinically important thymidine monophosphate analogues to the corresponding diphosphates, we solved the crystal structures of the enzyme, with either ADP or the ATP analogue AppNHp at the phosphoryl donor site, in complex with TMP, AZTMP (previous work), NH2TMP, d4TMP, ddTMP, and FLTMP (this work) at the phosphoryl acceptor site. In conjunction with steady-state kinetic data, our structures shed light on the effect of 3'-substitutions in the nucleoside monophosphate (NMP) sugar moiety on the catalytic rate. We observe a direct correlation between the rate of phosphorylation of an NMP and its ability to induce a closing of the enzyme's phosphate-binding loop (P-loop). Our results show the drastic effects that slight modifications of the substrates exert on the enzyme's conformation and, hence, activity and suggest the type of substitutions that are compatible with efficient phosphorylation by TMPK.
About this StructureAbout this Structure
1NN5 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structures of human thymidylate kinase in complex with prodrugs: implications for the structure-based design of novel compounds., Ostermann N, Segura-Pena D, Meier C, Veit T, Monnerjahn C, Konrad M, Lavie A, Biochemistry. 2003 Mar 11;42(9):2568-77. PMID:12614151 Page seeded by OCA on Sat May 3 02:44:10 2008