View source for 4zyv


==Human GAR transformylase in complex with GAR and N-({5-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)butyl]thiophen-2-yl}carbonyl)-L-glutamic acid (AGF71)==
<StructureSection load='4zyv' size='340' side='right'caption='[[4zyv]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4zyv]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZYV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZYV FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.053&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G71:N-({5-[4-(2-AMINO-4-OXO-4,7-DIHYDRO-1H-PYRROLO[2,3-D]PYRIMIDIN-6-YL)BUTYL]THIOPHEN-2-YL}CARBONYL)-L-GLUTAMIC+ACID'>G71</scene>, <scene name='pdbligand=GAR:GLYCINAMIDE+RIBONUCLEOTIDE'>GAR</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4zyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zyv OCA], [https://pdbe.org/4zyv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zyv RCSB], [https://www.ebi.ac.uk/pdbsum/4zyv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zyv ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PUR2_HUMAN PUR2_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Pemetrexed and methotrexate are antifolates used for cancer chemotherapy and inflammatory diseases. These agents have toxic side effects resulting, in part, from nonspecific cellular transport by the reduced folate carrier (RFC), a ubiquitously expressed facilitative transporter. We previously described 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine antifolates with modifications of the side chain linker and aromatic ring that are poor substrates for RFC but are efficiently transported via folate receptors (FRs) and the proton-coupled folate transporter (PCFT). These targeted antifolates are cytotoxic in vitro toward FR- and PCFT-expressing tumor cells and in vivo with human tumor xenografts in immune-compromised mice, reflecting selective cellular uptake. Antitumor efficacy is due to inhibition of glycinamide ribonucleotide (GAR) formyltransferase (GARFTase) activity in de novo synthesis of purine nucleotides. This study used purified human GARFTase (formyltransferase domain) to assess in vitro inhibition by eight novel thieno- and pyrrolo[2,3-d]pyrimidine antifolates. Seven analogues (AGF23, AGF71, AGF94, AGF117, AGF118, AGF145, and AGF147) inhibited GARFTase with Ki values in the low- to mid-nanomolar concentration range, whereas AGF50 inhibited GARFTase with micromolar potency similar to that of PMX. On the basis of crystal structures of ternary complexes with GARFTase, beta-GAR, and the monoglutamyl antifolates, differences in inhibitory potencies correlated well with antifolate binding and the positions of the terminal carboxylates. Our data provide a mechanistic basis for differences in inhibitory potencies between these novel antifolates and a framework for future structure-based drug design. These analogues could be more efficacious than clinically used antifolates, reflecting their selective cellular uptake by FRs and PCFT and potent GARFTase inhibition.

Structural and Enzymatic Analysis of Tumor-Targeted Antifolates That Inhibit Glycinamide Ribonucleotide Formyltransferase.,Deis SM, Doshi A, Hou Z, Matherly LH, Gangjee A, Dann CE 3rd Biochemistry. 2016 Aug 16;55(32):4574-82. doi: 10.1021/acs.biochem.6b00412. Epub , 2016 Aug 3. PMID:27439469<ref>PMID:27439469</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4zyv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Dann III CE]]
[[Category: Deis SM]]