2cxp: Difference between revisions
New page: left|200px<br /><applet load="2cxp" size="450" color="white" frame="true" align="right" spinBox="true" caption="2cxp, resolution 1.70Å" /> '''Crystal structure of... |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:2cxp.gif|left|200px]]<br /><applet load="2cxp" size=" | [[Image:2cxp.gif|left|200px]]<br /><applet load="2cxp" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2cxp, resolution 1.70Å" /> | caption="2cxp, resolution 1.70Å" /> | ||
'''Crystal structure of mouse AMF / A5P complex'''<br /> | '''Crystal structure of mouse AMF / A5P complex'''<br /> | ||
==Overview== | ==Overview== | ||
Autocrine motility factor (AMF), a tumor-secreted cytokine, stimulates | Autocrine motility factor (AMF), a tumor-secreted cytokine, stimulates cell migration in vitro and metastasis in vivo. AMF is identical to the extracellular cytokines neuroleukin and maturation factor and, interestingly, to the intracellular enzyme phosphoglucose isomerase. The cytokine activity of AMF is inhibited by carbohydrate phosphate compounds as they compete for AMF binding with the carbohydrate moiety of the AMF receptor (AMFR), which is a glycosylated seven transmembrane helix protein. Here, we report the first comprehensive high-resolution crystal structure analyses of the inhibitor-free form and the eight types of inhibitor (phosphate, erythrose 4-phosphate (E4P), arabinose 5-phosphate (A5P), sorbitol 6-phosphate (S6P), 6-phosphogluconic acid (6PGA), fructose 6-phosphate (F6P), glucose 6-phosphate (G6P), or mannose 6-phosphate (M6P)) complexes of mouse AMF (mAMF). We assayed the inhibitory activities of these inhibitors against the cytokine activity of mAMF. The inhibitory activities of the six-carbon sugars (G6P, F6P, M6P, and 6PGA) were found to be significantly higher than those of the four or five-carbon sugars (E4P or A5P). The inhibitory activities clearly depend on the length of the inhibitor molecules. A structural comparison revealed that a water-mediated hydrogen bond between one end of the inhibitor and a rigid portion of the protein surface in the shorter-chain inhibitor (E4P) complex is replaced by a direct hydrogen bond in the longer-chain inhibitor (6PGA) complex. Thus, to obtain a new compound with higher inhibitory activities against AMF, water molecules at the inhibitor binding site of AMF should be replaced by a functional group of inhibitors in order to introduce direct interactions with the protein surface. The present structure-activity relationship studies will be valuable not only for designing more effective AMF inhibitors but also for studying general protein-inhibitor interactions. | ||
==About this Structure== | ==About this Structure== | ||
2CXP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with A5P and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Glucose-6-phosphate_isomerase Glucose-6-phosphate isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.1.9 5.3.1.9] Full crystallographic information is available from [http:// | 2CXP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=A5P:'>A5P</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Glucose-6-phosphate_isomerase Glucose-6-phosphate isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.3.1.9 5.3.1.9] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CXP OCA]. | ||
==Reference== | ==Reference== | ||
| Line 20: | Line 20: | ||
[[Category: Naba, N.]] | [[Category: Naba, N.]] | ||
[[Category: Nagase, H.]] | [[Category: Nagase, H.]] | ||
[[Category: Nakamura, K | [[Category: Nakamura, K T.]] | ||
[[Category: Raz, A.]] | [[Category: Raz, A.]] | ||
[[Category: Shiraiwa, K.]] | [[Category: Shiraiwa, K.]] | ||
| Line 28: | Line 28: | ||
[[Category: isomerase]] | [[Category: isomerase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:53:25 2008'' | ||
Revision as of 17:53, 21 February 2008
|
Crystal structure of mouse AMF / A5P complex
OverviewOverview
Autocrine motility factor (AMF), a tumor-secreted cytokine, stimulates cell migration in vitro and metastasis in vivo. AMF is identical to the extracellular cytokines neuroleukin and maturation factor and, interestingly, to the intracellular enzyme phosphoglucose isomerase. The cytokine activity of AMF is inhibited by carbohydrate phosphate compounds as they compete for AMF binding with the carbohydrate moiety of the AMF receptor (AMFR), which is a glycosylated seven transmembrane helix protein. Here, we report the first comprehensive high-resolution crystal structure analyses of the inhibitor-free form and the eight types of inhibitor (phosphate, erythrose 4-phosphate (E4P), arabinose 5-phosphate (A5P), sorbitol 6-phosphate (S6P), 6-phosphogluconic acid (6PGA), fructose 6-phosphate (F6P), glucose 6-phosphate (G6P), or mannose 6-phosphate (M6P)) complexes of mouse AMF (mAMF). We assayed the inhibitory activities of these inhibitors against the cytokine activity of mAMF. The inhibitory activities of the six-carbon sugars (G6P, F6P, M6P, and 6PGA) were found to be significantly higher than those of the four or five-carbon sugars (E4P or A5P). The inhibitory activities clearly depend on the length of the inhibitor molecules. A structural comparison revealed that a water-mediated hydrogen bond between one end of the inhibitor and a rigid portion of the protein surface in the shorter-chain inhibitor (E4P) complex is replaced by a direct hydrogen bond in the longer-chain inhibitor (6PGA) complex. Thus, to obtain a new compound with higher inhibitory activities against AMF, water molecules at the inhibitor binding site of AMF should be replaced by a functional group of inhibitors in order to introduce direct interactions with the protein surface. The present structure-activity relationship studies will be valuable not only for designing more effective AMF inhibitors but also for studying general protein-inhibitor interactions.
About this StructureAbout this Structure
2CXP is a Single protein structure of sequence from Mus musculus with and as ligands. Active as Glucose-6-phosphate isomerase, with EC number 5.3.1.9 Full crystallographic information is available from OCA.
ReferenceReference
Crystal structures of mouse autocrine motility factor in complex with carbohydrate phosphate inhibitors provide insight into structure-activity relationship of the inhibitors., Tanaka N, Haga A, Naba N, Shiraiwa K, Kusakabe Y, Hashimoto K, Funasaka T, Nagase H, Raz A, Nakamura KT, J Mol Biol. 2006 Feb 17;356(2):312-24. Epub 2005 Dec 9. PMID:16375918
Page seeded by OCA on Thu Feb 21 16:53:25 2008