Bhattacharje Gourab, Ghosh Amit, Das Amit Kumar
Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
School of Energy Science and Engineering, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
ACS Omega. 2022 Jun 1;7(23):19288-19304. doi: 10.1021/acsomega.2c00832. eCollection 2022 Jun 14.
Glycolipids like phosphatidylinositol hexamannosides (PIM) and lipoglycans, such as lipomannan (LM) and lipoarabinomannan (LAM), play crucial roles in virulence, survival, and antibiotic resistance of various mycobacterial species. Phosphatidyl-myo-inositol mannosyltransferase A (PimA) catalyzes the transfer of the mannose moiety (M) from GDP-mannose (GDPM) to phosphatidyl-myo-inositol (PI) to synthesize GDP and phosphatidyl-myo-inositol monomannoside (PIM). This PIM is mannosylated, acylated, and further modified to give rise to the higher PIMs, LM, and LAM. It is yet to be known how PI, PIM, PI-GDPM, and PIM-GDP interact with PimA. Here, we report the docked structures of PI and PIM to understand how the substrates and the products interact with PimA. Using molecular dynamics (MD) simulations for 300 ns, we have investigated how various ligand-bound conformations change the dynamics of PimA. Our studies demonstrated the "open to closed" motions of PimA. We observed that PimA is least dynamic when bound to both GDPM and PI. MD simulations indicated that the loop residues 59-70 and the α-helical residues 73-86 of PimA play important roles while interacting with both PI and PIM. MD analyses also suggested that the residues Y9, P59, R68, L69, N97, R196, R201, K202, and R228 of PimA play significant roles in the mannose transfer reaction. Overall, docking studies and MD simulations provide crucial insights to design future therapeutic drugs against mycobacterial PimA.
糖脂如磷脂酰肌醇六甘露糖苷（PIM）和脂多糖，如脂甘露聚糖（LM）和脂阿拉伯甘露聚糖（LAM），在各种分枝杆菌属的毒力、存活和抗生素抗性中发挥着关键作用。磷脂酰 - 肌醇甘露糖基转移酶A（PimA）催化甘露糖部分（M）从GDP - 甘露糖（GDPM）转移至磷脂酰 - 肌醇（PI），以合成GDP和磷脂酰 - 肌醇单甘露糖苷（PIM）。该PIM经过甘露糖基化、酰化，并进一步修饰以产生更高阶的PIM、LM和LAM。目前尚不清楚PI、PIM、PI - GDPM和PIM - GDP如何与PimA相互作用。在此，我们报告了PI和PIM的对接结构，以了解底物和产物如何与PimA相互作用。通过300纳秒的分子动力学（MD）模拟，我们研究了各种配体结合构象如何改变PimA的动力学。我们的研究证明了PimA的“开放到闭合”运动。我们观察到当与GDPM和PI都结合时，PimA的动力学最小。MD模拟表明，PimA的环残基59 - 70和α - 螺旋残基73 - 86在与PI和PIM相互作用时发挥重要作用。MD分析还表明，PimA的残基Y9、P59、R68、L69、N97、R196、R201、K202和R228在甘露糖转移反应中发挥重要作用。总体而言，对接研究和MD模拟为设计针对分枝杆菌PimA的未来治疗药物提供了关键见解。
