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Biodegradation of Starch
Published in Jean-Luc Wertz, Bénédicte Goffin, Starch in the Bioeconomy, 2020
Jean-Luc Wertz, Bénédicte Goffin
The characteristic sequence constitutes the phosphate-binding loop, or the so-called P-loop, where the main chain nitrogens and the guanidinium group of the arginine residue are oriented as to coordinate the equatorial oxygens of the phosphate group during substrate binding and catalysis. The geometry of the P-loop provides a perfect complementary structure to the two transition states of the reaction and the bidentate interaction provided by the arginine side chain is essential for catalysis.
Structure of linear motors
Published in Peixuan Guo, Zhengyi Zhao, Biomotors: Linear, Rotation, and Revolution Motion Mechanisms, 2017
The nucleotide binding pocket of myosin coordinates nucleotide binding, cleavage of the phosphoanhydride bond of ATP, and the sequential release of products that is crucial for converting chemical energy into mechanical work (Lymn & Taylor, 1971; Eisenberg & Greene, 1980; De La Cruz & Ostap, 2004). The ATP molecule is coordinated in the NBP by three highly conserved structural elements, switch I, switch II, and the P-loop (Kull et al., 1998; Vale & Milligan, 2000) (Figure 4.2). The family of P-loop NTPases, including G-proteins, kinesins, and myosins, is thought to have evolved from a common ancestor (Kull et al., 1998). Switch I has been reported to be an important element that coordinates the sequential release of products and transmits information from the NBP to the actin binding cleft in myosins (Kintses et al., 2007). Switch II is another well-conserved element that forms a salt bridge with Switch I and interacts with the γ-phosphate of ATP, which is essential for catalysis (Sasaki et al., 1998; Onishi et al., 2002). Coordination of the α and β phosphates of ATP is accomplished by the P loop. The coordination of magnesium (Mg) is through the oxygen on the β and γ phosphates and several residues in the switch I region (Rayment et al., 1996; Swenson et al., 2014). The γ-phosphate of ATP plays a central role in the interaction of the switch elements and the P-loop with ATP. This explains why ATP, and not ADP, can lead to the weak actin-binding state of myosin and also induces the recovery stroke of the lever arm. The binding of ATP to the active site results in the switch elements adopting a “closed” conformation, which leads to an opening of the actin binding cleft (Coureux et al., 2004). The closing of the switch elements also gets communicated to the lever-arm region via the relay helix, which results in formation of the pre-powerstroke state (Fischer et al., 2005; Malnasi-Csizmadia et al., 2005; Nesmelov et al., 2011) (Figure 4.2). Actin binding can stimulate the release of ADP by changing the conformation of switch I and disrupting magnesium coordination (Rosenfeld et al., 2005). It has been speculated that the coupling associated with actin and ADP binding requires the coordination of bound magnesium (Hannemann et al., 2005; Rosenfeld et al., 2005; Swenson et al., 2014). Moreover, two different states of switch I have been reported when MgADP is bound in the pocket, and both of these states bind ADP differently (Hannemann et al., 2005). In rapidly contracting muscle fibers, ADP release has been shown to be a major determinant of the maximum shortening velocity and has been speculated to be a central step for sensing load on the myosin crossbridge, thus making it a strain-sensitive step (Nyitrai & Geeves, 2004). Since the lever arm senses the load, there must be allosteric communication between the lever arm and the NBP to modulate the load-dependent release of ADP.
Molecular dynamics simulation study on the inhibitory mechanism of RIPK1 by 4,5-dihydropyrazole derivatives
Published in Molecular Physics, 2023
Yurou Zhang, Song Wang, Aimin Ren, Shanshan Guan, E Jingwen, Zhijian Luo, Zhijie Yang, Xinyue Zhang, Juan Du, Hao Zhang
Figure 12 shows the relationship between the protein region near the P-loop, Lys45, and the position of the inhibitor in the four complexes. In complex 2-4, the Glu19-Leu23 segment and its adjacent Lys30-Ala34 segment formed the β1 and β2 sheets. p-loop was the loop connecting these two sheets. However, Glu19-Leu23 in complex 1 did not form a β1 sheet (previous secondary structure analysis could confirm that this phenomenon was prevalent during the simulation). After careful observation, it was discovered that this may be related to the relative positions of the Lys30 side chain and the Glu19-Leu23. With the orientation in the figure, Lys30 is located on the β2 sheet with its side chain pointing to the Glu19-Leu23 side. When Glu19-Leu23 crosses from behind the Lys30 side chain (complex 2-4), it forms parallel hydrogen bonds with the β2 sheet and eventually transforms into the β1 sheet. when it crosses from the front of the Lys30 side chain (complex 1), it cannot form the β1 sheet due to the spatial site block of Lys30. As noted previously, this region contained residues related to RIPK1 substrate recognition (Ser25 and Phe28), and failure to form a stable β1 sheet would likely affect the stability of substrate recognition by the enzyme and ultimately reduce the enzyme activity. The strongest inhibitory ability of inhibitor 1 may be related to this. The reason for the different position relationships between Lys30 and the Glu19-Leu23 was mainly influenced by the different positions of Lys45. As mentioned above, when the inhibitor had a different 1-substituent, it may affect the side chain of Lys45 differently, resulting in different hydrogen bonds with Gly29 or Lys30 (as shown in Figure 12). This variation in hydrogen bond formation causes the atoms in Lys30 to point in different directions on the peptide planes, which ultimately leads to different orientations of the side chains and consequently affects the formation of the β1 sheet.