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| | {{STRUCTURE_1n3i| PDB=1n3i | SCENE= }} | | {{STRUCTURE_1n3i| PDB=1n3i | SCENE= }} |
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| - | '''Crystal Structure of Mycobacterium tuberculosis PNP with transition state analog DADMe-ImmH'''
| + | ===Crystal Structure of Mycobacterium tuberculosis PNP with transition state analog DADMe-ImmH=== |
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| - | ==Overview==
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| - | Stable chemical analogues of enzymatic transition states are imperfect mimics since they lack the partial bond character of the transition state. We synthesized structural variants of the Immucillins as transition state analogues for purine nucleoside phosphorylase and characterized them with the enzyme from Mycobacterium tuberculosis (MtPNP). PNPs form transition states with ribooxacarbenium ion character and catalyze nucleophilic displacement reactions by migration of the cationic ribooxacarbenium carbon between the enzymatically immobilized purine and phosphate nucleophiles. As bond-breaking progresses, carbocation character builds on the ribosyl group, the distance between the purine and the carbocation increases, and the distance between carbocation and phosphate anion decreases. Transition state analogues were produced with carbocation character and increased distance between the ribooxacarbenium ion and the purine mimics by incorporating a methylene bridge between these groups. Immucillin-H (ImmH), DADMe-ImmH, and DADMe-ImmG mimic the transition state of MtPNP and are slow-onset, tight-binding inhibitors of MtPNP with equilibrium dissociation constants of 650, 42, and 24 pM. Crystal structures of MtPNP complexes with ImmH and DADMe-ImmH reveal an ion-pair between the inhibitor cation and the nucleophilic phosphoryl anion. The stronger ion-pair (2.7 A) is found with DADMe-ImmH. The position of bound ImmH resembles the substrate side of the transition state barrier, and DADMe-ImmH more closely resembles the product side of the barrier. The ability to probe both substrate and product sides of the transition state barrier provides expanded opportunities to explore transition state analogue design in N-ribosyltransferases. This approach has resulted in the highest affinity transition state analogues known for MtPNP.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_12755607}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 12755607 is the PubMed ID number. |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Transition state complex]] | | [[Category: Transition state complex]] |
| | [[Category: Trimer]] | | [[Category: Trimer]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:02:43 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 12:22:34 2008'' |
Revision as of 09:22, 29 July 2008
Template:STRUCTURE 1n3i
Crystal Structure of Mycobacterium tuberculosis PNP with transition state analog DADMe-ImmH
Template:ABSTRACT PUBMED 12755607
About this Structure
1N3I is a Single protein structure of sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.
Reference
Over-the-barrier transition state analogues and crystal structure with Mycobacterium tuberculosis purine nucleoside phosphorylase., Lewandowicz A, Shi W, Evans GB, Tyler PC, Furneaux RH, Basso LA, Santos DS, Almo SC, Schramm VL, Biochemistry. 2003 May 27;42(20):6057-66. PMID:12755607
Page seeded by OCA on Tue Jul 29 12:22:34 2008
