Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

3-SN-PHOSPHATIDYLETHANOLAMINE; 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE

Cytochrome b-c1 complex subunit 1, mitochondrial

Cytochrome b-c1 complex subunit 2, mitochondrial

Cytochrome c1, heme protein, mitochondrial

Cytochrome b-c1 complex subunit Rieske, mitochondrial

Complex III subunit 1,Core protein I,Ubiquinol-cytochrome-c reductase complex core protein 1

Complex III subunit 2,Core protein II,Ubiquinol-cytochrome-c reductase complex core protein 2

Complex III subunit 3,Complex III subunit CYTB,Complex III subunit III,Cytochrome b-c1 complex subunit 3,Cytochrome b-c1 complex subunit CYTB,Ubiquinol-cytochrome-c reductase complex cytochrome b subunit

Complex III subunit 4,Complex III subunit IV,Cytochrome b-c1 complex subunit 4,Ubiquinol-cytochrome-c reductase complex cytochrome c1 subunit,Cytochrome c-1

Complex III subunit 5,Rieske iron-sulfur protein,RISP,Ubiquinol-cytochrome c reductase iron-sulfur subunit

Complex III subunit 6,Complex III subunit VI,Cytochrome c1 non-heme 17 kDa protein,Mitochondrial hinge protein,Ubiquinol-cytochrome c reductase complex 17 kDa protein

Complex III subunit 7,Complex III subunit VII,Ubiquinol-cytochrome c reductase c reductase complex 14 kDa protein

Complex III subunit 8,Complex III subunit VII,Ubiquinol-cytochrome c reductase complex 11 kDa protein,Ubiquinol-cytochrome c reductase complex ubiquinone-binding protein QP-C

Complex III subunit 9,Complex III subunit X,Cytochrome c1 non-heme 7.3 kDa protein,Ubiquinol-cytochrome c reductase complex 7.3 kDa protein

AEVTQLSNGIVVATEHNPSAHTASVGVVFGSGAANENPYNNGVSNLWKNIFLSKENSAVAAKEGLALSSNISRDFQSYIV
SSLPGSTDKSLDFLNQSFIQQKANLLSSSNFEATKKSVLKQVQDFEDNDHPNRVLEHLHSTAFQNTPLSLPTRGTLESLE
NLVVADLESFANNHFLNSNAVVVGTGNIKHEDLVNSIESKNLSLQTGTKPVLKKKAAFLGSEVRLRDDTLPKAWISLAVE
GEPVNSPNYFVAKLAAQIFGSYNAFEPASRLQGIKLLDNIQEYQLCDNFNHFSLSYKDSGLWGFSTATRNVTMIDDLIHF
TLKQWNRLTISVTDTEVERAKSLLKLQLGQLYESGNPVNDANLLGAEVLIKGSKLSLGEAFKKIDAITVKDVKAWAGKRL
WDQDIAIAGTGQIEGLLDYMRIRSDMSMMRW

LTVSARDAPTKISTLAVKVHGGSRYATKDGVAHLLNRFNFQNTNTRSALKLVRESELLGGTFKSTLDREYITLKATFLKD
DLPYYVNALADVLYKTAFKPHELTESVLPAARYDYAVAEQCPVKSAEDQLYAITFRKGLGNPLLYDGVERVSLQDIKDFA
DKVYTKENLEVSGENVVEADLKRFVDESLLSTLPAGKSLVSKSEPKFFLGEENRVRFIGDSVAAIGIPVNKASLAQYEVL
ANYLTSALSELSGLISSAKLDKFTDGGLFTLFVRDQDSAVVSSNIKKIVADLKKGKDLSPAINYTKLKNAVQNESVSSPI
ELNFDAVKDFKLGKFNYVAVGDVSNLPYLDEL

MAFRKSNVYLSLVNSYIIDSPQPSSINYWWNMGSLLGLCLVIQIVTGIFMAMHYSSNIELAFSSVEHIMRDVHNGYILRY
LHANGASFFFMVMFMHMAKGLYYGSYRSPRVTLWNVGVIIFILTIATAFLGYCCVYGQMSHWGATVITNLFSAIPFVGND
IVSWLWGGFSVSNPTIQRFFALHYLVPFIIAAMVIMHLMALHIHGSSNPLGITGNLDRIPMHSYFIFKDLVTVFLFMLIL
ALFVFYSPNTLGHPDNYIPGNPLVTPASIVPEWYLLPFYAILRSIPDKLLGVITMFAAILVLLVLPFTDRSVVRGNTFKV
LSKFFFFIFVFNFVLLGQIGACHVEVPYVLMGQIATFIYFAYFLIIVPVISTIENVLFYIGRVNK

MTAAEHGLHAPAYAWSHNGPFETFDHASIRRGYQVYREVCAACHSLDRVAWRTLVGVSHTNEEVRNMAEEFEYDDEPDEQ
GNPKKRPGKLSDYIPGPYPNEQAARAANQGALPPDLSLIVKARHGGCDYIFSLLTGYPDEPPAGVALPPGSNYNPYFPGG
SIAMARVLFDDMVEYEDGTPATTSQMAKDVTTFLNWCAEPEHDERKRLGLKTVIILSSLYLLSIWVKKFKWAGIKTRKFV
FNPPKPRK

KSTYRTPNFDDVLKENNDADKGRSYAYFMVGAMGLLSSAGAKSTVETFISSMTATADVLAMAKVEVNLAAIPLGKNVVVK
WQGKPVFIRHRTPHEIQEANSVDMSALKDPQTDADRVKDPQWLIMLGICTHLGCVPIGEAGDFGGWFCPCHGSHYDISGR
IRKGPAPLNLEIPAYEFDGDKVIVG

PQSFTSIARIGDYILKSPVLSKLCVPVANQFINLAGYKKLGLKFDDLIAEENPIMQTALRRLPEDESYARAYRIIRAHQT
ELTHHLLPRNEWIKAQEDVPYLLPYILEAEAAAKEKDELDNIEVSK

GPPSGKTYMGWWGHMGGPKQKGITSYAVSPYAQKPLQGIFHNAVFNSFRRFKSQFLYVLIPAGIYWYWWKNGNEYNEFLY
SKAGREELERVNV

EVKLQESGAGLVQPSQSLSLTCSVTGYSITSGYYWNWIRLFPGNKLEWVGYISNVGDNNYNPSLKDRLSITRDTSKNQFF
LKLNSVTTEDTATYYCARSEYYSVTGYAMDYWGQGTTVTVSSAWRHP

DIELTQTPVSLAASLGDRVTISCRASQDINNFLNWYQQKPDGTIKLLIYYTSRLHAGVPSRFSGSGSGTDYSLTISNLEP
EDIATYFCQHHIKFPWTFGAGTKLEIK

Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

polyethylene glycol 4000, DMSO, Sucrose, Potassium phosphate, n-undecyl-?-D-maltopyranoside, atovaquone

Excellence Initiative of the German Federal and State Governments

Author states that the structure was determined by molecular replacement and used the high-resolution structure of yeast cyt bc1 complex (pdb 3cx5) as basis for refinement. Quality of x-ray diffraction data for the new structure is limited and some poorly resolved loops were set to zero occupancy. The large complex covers a wide range of B-factors, with the highest in the matrix core subunits (chains A and B) and the lowest in the membrane integral subunit cytochrome b (chain C). In former structures obtained at room-temperature , such as 2KB9 at 2.3 angstrom, B factors range from above140 for chain A to below 30 for chain C. In this structure, the overall B-factors are lower but cover a similar range with very low up to zero B factors in the best ordered regions.
Cytochrome bc1 complex, Membrane protein complex, antimalarial drug, inhibitor, OXIDOREDUCTASE-INHIBITOR complex

AEVTQLSNGIVVATEHNPSAHTASVGVVFGSGAANENPYNNGVSNLWKNIFLSKENSAVAAKEGLALSSNISRDFQSYIV
SSLPGSTDKSLDFLNQSFIQQKANLLSSSNFEATKKSVLKQVQDFEENDHPNRVLEHLHSTAFQNTPLSLPTRGTLESLE
NLVVADLESFANNHFLNSNAVVVGTGNIKHEDLVNSIESKNLSLQTGTKPVLKKKAAFLGSEVRLRDDTLPKAWISLAVE
GEPVNSPNYFVAKLAAQIFGSYNAFEPASRLQGIKLLDNIQEYQLCDNFNHFSLSYKDSGLWGFSTATRNVTMIDDLIHF
TLKQWNRLTISVTDTEVERAKSLLKLQLGQLYESGNPVNDANLLGAEVLIKGSKLSLGEAFKKIDAITVKDVKAWAGKRL
WDQDIAIAGTGQIEGLLDYMRIRSDMSMMRW