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首页> 外文期刊>Biochemistry >Crystal Structure of a Complex between the Actinoinadura R39 no-Peptidase and aPeptidoglycan-mimetic Boronate Inhibitor: Interpretation of a Transition StateAnalogue in Terms of Catalytic Mechanismt
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Crystal Structure of a Complex between the Actinoinadura R39 no-Peptidase and aPeptidoglycan-mimetic Boronate Inhibitor: Interpretation of a Transition StateAnalogue in Terms of Catalytic Mechanismt

机译：Actinoinadura R39无肽酶和拟肽聚糖模拟硼酸盐抑制剂之间的复合物的晶体结构：过渡态类似物的催化机理的解释。

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The Actinomadura R39 Do-peptidase is a bacterial low molecular weight class C penicillin-binding protein. It has previously been shown to catalyze hydrolysis and aminolysis of small D-alanyl-o-alanine terminating peptides, especially those with a side chain that mimics the amino terminus of the stem peptide precursor to the bacterial cell wall. This paper describes the synthesis of (D-a-aminopimelylamino)-D-1- ethylboronic acid, designed to be a peptidoglycan-mimetic transition state analogue inhibitor of the R39 Do-peptidase. The boronate was found to be a potent inhibitor of the peptidase with a K_i value of 32 ± 6 nM. Since it binds some 30 times more strongly than the analogous peptide substrate, the boronate may well be a transition state analogue. A crystal structure of the inhibitory complex shows the boronate covalently bound to the nucleophilic active site Ser 49. The aminopimelyl side chain is bound into the site previously identified as specific for this moiety. One boronate oxygen is held in the oxyanion hole; the other, occupying the leaving group site of acylation or the nucleophile site of deacylation, appears to be hydrogen-bonded to the hydroxyl group of Ser 298. The Ser 49 oxygen appears to be hydrogen bonded to Lys 52. If it is assumed that this structure does resemble a high-energy tetrahedral intermediate in catalysis, it seems likely that Ser 298 participates as part of a proton transfer chain initiated by Lys 52 or Lys 410 as the primary proton donor! acceptor. The structure, therefore, supports a particular class of mechanism that employs this proton transfer device.
机译：猕猴桃R39 Do肽酶是一种细菌性低分子量C类青霉素结合蛋白。先前已显示出它催化小的D-丙氨酰-o-丙氨酸终止肽的水解和氨解，特别是那些具有模拟干肽前体至细菌细胞壁氨基端的侧链的肽。本文介绍了（D-a-氨基庚二酰氨基）-D-1-乙基硼酸的合成，该化合物设计为R39 Do-肽酶的肽聚糖模拟过渡态类似物抑制剂。发现硼酸酯是肽酶的有效抑制剂，其K_i值为32±6nM。由于它的结合力是类似肽底物的30倍，因此硼酸酯很可能是过渡态类似物。抑制性复合物的晶体结构显示出硼酸酯共价键合到亲核活性位点Ser49。氨基庚二烯侧链结合到先前鉴定为对该部分特异的位点。在氧阴离子孔中保留一种硼氧。另一个占据酰化的离去基团位点或去酰化的亲核基团位点，似乎与Ser 298的羟基氢键合。Ser49氧似乎与Lys 52氢键合。其结构确实类似于催化中的高能四面体中间体，Ser 298似乎可能是作为主要质子供体的Lys 52或Lys 410引发的质子转移链的一部分！受体。因此，该结构支持采用该质子传递装置的特定类型的机构。

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