4cgo: Difference between revisions
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==Leishmania major N-myristoyltransferase in complex with a thienopyrimidine inhibitor== | |||
<StructureSection load='4cgo' size='340' side='right'caption='[[4cgo]], [[Resolution|resolution]] 1.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4cgo]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_major Leishmania major]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CGO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CGO 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]] 1.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6KV:3-[METHYL-[2-[METHYL-(1-METHYLPIPERIDIN-4-YL)AMINO]THIENO[3,2-D]PYRIMIDIN-4-YL]AMINO]PROPANENITRILE'>6KV</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MYA:TETRADECANOYL-COA'>MYA</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=4cgo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cgo OCA], [https://pdbe.org/4cgo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cgo RCSB], [https://www.ebi.ac.uk/pdbsum/4cgo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cgo ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q4Q5S8_LEIMA Q4Q5S8_LEIMA] Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The leishmaniases are a spectrum of global diseases of poverty associated with immune dysfunction and are the cause of high morbidity. Despite the long history of these diseases, no effective vaccine is available and the currently used drugs are variously compromised by moderate efficacy, complex side effects and the emergence of resistance. It is therefore widely accepted that new therapies are needed. N-Myristoyltransferase (NMT) has been validated pre-clinically as a target for the treatment of fungal and parasitic infections. In a previously reported high-throughput screening program, a number of hit compounds with activity against NMT from Leishmania donovani have been identified. Here, high-resolution crystal structures of representative compounds from four hit series in ternary complexes with myristoyl-CoA and NMT from the closely related L. major are reported. The structures reveal that the inhibitors associate with the peptide-binding groove at a site adjacent to the bound myristoyl-CoA and the catalytic alpha-carboxylate of Leu421. Each inhibitor makes extensive apolar contacts as well as a small number of polar contacts with the protein. Remarkably, the compounds exploit different features of the peptide-binding groove and collectively occupy a substantial volume of this pocket, suggesting that there is potential for the design of chimaeric inhibitors with significantly enhanced binding. Despite the high conservation of the active sites of the parasite and human NMTs, the inhibitors act selectively over the host enzyme. The role of conformational flexibility in the side chain of Tyr217 in conferring selectivity is discussed. | |||
Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors.,Brannigan JA, Roberts SM, Bell AS, Hutton JA, Hodgkinson MR, Tate EW, Leatherbarrow RJ, Smith DF, Wilkinson AJ IUCrJ. 2014 Jun 17;1(Pt 4):250-60. doi: 10.1107/S2052252514013001. eCollection, 2014 Jul 1. PMID:25075346<ref>PMID:25075346</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4cgo" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Leishmania major]] | |||
[[Category: Bell AS]] | |||
[[Category: Brannigan JA]] | |||
[[Category: Hutton JA]] | |||
[[Category: Leatherbarrow RJ]] | |||
[[Category: Roberts SM]] | |||
[[Category: Smith DF]] | |||
[[Category: Tate EW]] | |||
[[Category: Wilkinson AJ]] | |||
Latest revision as of 14:12, 9 May 2024
Leishmania major N-myristoyltransferase in complex with a thienopyrimidine inhibitorLeishmania major N-myristoyltransferase in complex with a thienopyrimidine inhibitor
Structural highlights
FunctionQ4Q5S8_LEIMA Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity). Publication Abstract from PubMedThe leishmaniases are a spectrum of global diseases of poverty associated with immune dysfunction and are the cause of high morbidity. Despite the long history of these diseases, no effective vaccine is available and the currently used drugs are variously compromised by moderate efficacy, complex side effects and the emergence of resistance. It is therefore widely accepted that new therapies are needed. N-Myristoyltransferase (NMT) has been validated pre-clinically as a target for the treatment of fungal and parasitic infections. In a previously reported high-throughput screening program, a number of hit compounds with activity against NMT from Leishmania donovani have been identified. Here, high-resolution crystal structures of representative compounds from four hit series in ternary complexes with myristoyl-CoA and NMT from the closely related L. major are reported. The structures reveal that the inhibitors associate with the peptide-binding groove at a site adjacent to the bound myristoyl-CoA and the catalytic alpha-carboxylate of Leu421. Each inhibitor makes extensive apolar contacts as well as a small number of polar contacts with the protein. Remarkably, the compounds exploit different features of the peptide-binding groove and collectively occupy a substantial volume of this pocket, suggesting that there is potential for the design of chimaeric inhibitors with significantly enhanced binding. Despite the high conservation of the active sites of the parasite and human NMTs, the inhibitors act selectively over the host enzyme. The role of conformational flexibility in the side chain of Tyr217 in conferring selectivity is discussed. Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors.,Brannigan JA, Roberts SM, Bell AS, Hutton JA, Hodgkinson MR, Tate EW, Leatherbarrow RJ, Smith DF, Wilkinson AJ IUCrJ. 2014 Jun 17;1(Pt 4):250-60. doi: 10.1107/S2052252514013001. eCollection, 2014 Jul 1. PMID:25075346[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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