An expanded view of ligandability in the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data.
An expanded view of ligandability in the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data.
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通过对大规模晶体学数据进行计算再分析，对变构酶 PTP1B 的配体性进行了扩展。
DOI：
10.1101/2024.01.05.574428
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Keedy,DanielA
中科院分区：
文献类型：
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作者：
Mehlman,TamarSkaist;Ginn,HelenM;Keedy,DanielA
最近出现的晶体学小分子片段筛选提供了机会，从一个单一的高通量实验中获得前所未有的数量的配体结合蛋白质晶体结构，映射蛋白质表面的配位能力，并确定有用的化学立足点，基于结构的药物设计。然而，由于大多数片段的低结合亲和力，从晶体学数据集中检测结合的片段一直是一个挑战。在这里，我们报告了PTP1B的59个新配体晶体结构中的65个新片段命中，PTP1B是糖尿病和癌症的“不可药物化”治疗靶酶。这些结构是通过对来自大型晶体屏幕的数据进行计算分析而获得的，证明了这种方法能够阐明蛋白质的许多（约50%以上）“隐藏”配体结合状态。我们的新结构包括在PTP1B中的一个新的结合位点中发现的片段命中，该位点相对于活性位点具有独特的位置，该位点验证了最近通过模拟确定的另一个新的结合位点，该位点连接相邻的变构位点，并且，也许最引人注目的是，通过先前未报道的分子内导管诱导长距离变构蛋白构象反应的片段。总而言之，我们的研究突出了晶体学数据的计算分析的实用性，公开了数十种高价值药物靶标的新配体结合结构，并确定了PTP1B中配位性和变构性的新方面。
The recent advent of crystallographic small-molecule fragment screening presents the opportunity to obtain unprecedented numbers of ligand-bound protein crystal structures from a single high-throughput experiment, mapping ligandability across protein surfaces and identifying useful chemical footholds for structure-based drug design. However, due to the low binding affinities of most fragments, detecting bound fragments from crystallographic datasets has been a challenge. Here we report a trove of 65 new fragment hits across 59 new liganded crystal structures for PTP1B, an “undruggable” therapeutic target enzyme for diabetes and cancer. These structures were obtained from computational analysis of data from a large crystallographic screen, demonstrating the power of this approach to elucidate many (~50% more) “hidden” ligand-bound states of proteins. Our new structures include a fragment hit found in a novel binding site in PTP1B with a unique location relative to the active site, one that validates another new binding site recently identified by simulations, one that links adjacent allosteric sites, and, perhaps most strikingly, a fragment that induces long-range allosteric protein conformational responses via a previously unreported intramolecular conduit. Altogether, our research highlights the utility of computational analysis of crystallographic data, makes publicly available dozens of new ligand-bound structures of a high-value drug target, and identifies novel aspects of ligandability and allostery in PTP1B.