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8q2b

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E. coli Adenylate Kinase variant D158A (AK D158A) showing significant changes to the stacking of catalytic arginine side chains

Structural highlights

8q2b is a 2 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.76Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

C3TLA2_ECOLX Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism.[HAMAP-Rule:MF_00235]

Publication Abstract from PubMed

This study explores ligand-driven conformational changes in adenylate kinase (AK), which is known for its open-to-close conformational transitions upon ligand binding and release. By utilizing string free energy simulations, we determine the free energy profiles for both enzyme opening and ligand release and compare them with profiles from the apoenzyme. Results reveal a three-step ligand release process, which initiates with the opening of the adenosine triphosphate-binding subdomain (ATP lid), followed by ligand release and concomitant opening of the adenosine monophosphate-binding subdomain (AMP lid). The ligands then transition to nonspecific positions before complete dissociation. In these processes, the first step is energetically driven by ATP lid opening, whereas the second step is driven by ATP release. In contrast, the AMP lid opening and its ligand release make minor contributions to the total free energy for enzyme opening. Regarding the ligand binding mechanism, our results suggest that AMP lid closure occurs via an induced-fit mechanism triggered by AMP binding, whereas ATP lid closure follows conformational selection. This difference in the closure mechanisms provides an explanation with implications for the debate on ligand-driven conformational changes of AK. Additionally, we determine an X-ray structure of an AK variant that exhibits significant rearrangements in the stacking of catalytic arginines, explaining its reduced catalytic activity. In the context of apoenzyme opening, the sequence of events is different. Here, the AMP lid opens first while the ATP lid remains closed, and the free energy associated with ATP lid opening varies with orientation, aligning with the reported AK opening and closing rate heterogeneity. Finally, this study, in conjunction with our previous research, provides a comprehensive view of the intricate interplay between various structural elements, ligands, and catalytic residues that collectively contribute to the robust catalytic power of the enzyme.

Elucidating Dynamics of Adenylate Kinase from Enzyme Opening to Ligand Release.,Nam K, Arattu Thodika AR, Grundstrom C, Sauer UH, Wolf-Watz M J Chem Inf Model. 2024 Jan 8;64(1):150-163. doi: 10.1021/acs.jcim.3c01618. Epub , 2023 Dec 20. PMID:38117131^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nam K, Arattu Thodika AR, Grundström C, Sauer UH, Wolf-Watz M. Elucidating Dynamics of Adenylate Kinase from Enzyme Opening to Ligand Release. J Chem Inf Model. 2024 Jan 8;64(1):150-163. PMID:38117131 doi:10.1021/acs.jcim.3c01618