PDBsum entry 2vz9

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Top Page protein ligands Protein-protein interface(s) links
Transferase PDB id
Protein chains
2081 a.a.
NAP ×4

References listed in PDB file
Key reference
Title The crystal structure of a mammalian fatty acid synthase.
Authors T.Maier, M.Leibundgut, N.Ban.
Ref. Science, 2008, 321, 1315-1322. [DOI no: 10.1126/science.1161269]
PubMed id 18772430
Mammalian fatty acid synthase is a large multienzyme that catalyzes all steps of fatty acid synthesis. We have determined its crystal structure at 3.2 angstrom resolution covering five catalytic domains, whereas the flexibly tethered terminal acyl carrier protein and thioesterase domains remain unresolved. The structure reveals a complex architecture of alternating linkers and enzymatic domains. Substrate shuttling is facilitated by flexible tethering of the acyl carrier protein domain and by the limited contact between the condensing and modifying portions of the multienzyme, which are mainly connected by linkers rather than direct interaction. The structure identifies two additional nonenzymatic domains: (i) a pseudo-ketoreductase and (ii) a peripheral pseudo-methyltransferase that is probably a remnant of an ancestral methyltransferase domain maintained in some related polyketide synthases. The structural comparison of mammalian fatty acid synthase with modular polyketide synthases shows how their segmental construction allows the variation of domain composition to achieve diverse product synthesis.
Figure 1.
Fig. 1. Structural overview. (A) Cartoon representation of mFAS, colored by domains as indicated. Linkers and linker domains are depicted in gray. Bound NADP^+ cofactors and the attachment sites for the disordered C-terminal ACP/TE domains are shown as blue and black spheres, respectively. The position of the pseudo-twofold dimer axis is depicted by an arrow; domains of the second chain are indicated by an appended prime. The lower panel (front view) shows a corresponding schematic diagram. (B) Top (upper panel) and bottom (lower panel) views, demonstrating the "S" shape of the modifying (upper) and condensing (lower) parts of mFAS. The pseudo-twofold axis is indicated by an ellipsoid. (C) Linear sequence organization of mFAS, at approximate sequence scale.
Figure 2.
Fig. 2. Interdomain linkers. (A) Surface representation of individual mFAS domains (front view), colored as in Fig. 1. Linking regions are shown as tubes. (B to E) Close-up views of individual linkers. The direction of view is indicated by arrowheads in (A). (B) Linker connecting the two subdomains of the DH domain only loosely interacts with the main body of the double hot dog fold. (C) Linkers in the KR/ER region are wrapped around the domains with close interactions to the domain surfaces and pronounced linker-linker contacts; they mediate interactions between the KR, KR, and ME domains. (D) Modifying upper and condensing lower parts of FAS are only in tangential contact in the region of the central connection. Few residues besides the connecting linkers mediate the sparse interactions via a small interface area. (E) MAT-DH linker meanders through a groove on the surface of the KS domain.
The above figures are reprinted by permission from the AAAs: Science (2008, 321, 1315-1322) copyright 2008.
Secondary reference #1
Title Architecture of mammalian fatty acid synthase at 4.5 a resolution.
Authors T.Maier, S.Jenni, N.Ban.
Ref. Science, 2006, 311, 1258-1262. [DOI no: 10.1126/science.1123248]
PubMed id 16513975
Full text Abstract
Figure 4.
Fig. 4. Active sites and reaction chamber. (A) Front view of FAS with ribbon representations of fitted domains colored as in Fig. 1. The overall shape is indicated by the outline of electron density; gray and blue colors of the outline mark the nonmodeled KS/MAT interconnection and suggested ACP/TE location, respectively. The positions of active sites in the two reaction chambers are indicated by solid white and blue spheres. Hollow spheres in domain colors that surround the active sites denote the length of the phosphopantheteine arm, reflecting how close ACP has to approach the individual domains during the catalytic cycle. The active sites are connected in order of the reaction sequence with distances between the active sites indicated for the left reaction chamber. (B) Side view into one reaction chamber as indicated by a white arrow in (A); for clarity, only surface representations of the fitted domains are shown. Active sites of fitted domains of one reaction chamber are indicated by a color gradient to white on the respective surfaces.
Figure 5.
Fig. 5. Interdomain hinges and conformational variability. For structural comparison, the FAS dimer is superimposed onto itself by applying the transformation relating the dimer of KS domains as indicated by an arrow. As a result, the left reaction chamber is transformed onto the right one and vice versa. The original orientation is shown in red, the transformed one in yellow. (A) Only secondary structural elements of the fitted domains are shown. Largest differences are observed for the positions of the KR and MAT domains at the periphery. The approximate position of the pseudo-twofold dimer axis is indicated by an arrow. (B) Experimental electron density is schematically shown as an outline. The positions of active sites are indicated by spheres, hinges by crossed circles. The left reaction chamber is considerably narrower than the right one with a difference of distances between the KR and MAT active sites of about 15 Å as indicated for the original orientation in red.
The above figures are reproduced from the cited reference with permission from the AAAs
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