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Matt Prior hit 60, from 90 balls with nine fours, but South Africa took England's last seven wickets for 134 runs.
Morne Morkel was the pick of the bowlers with figures of 4-74, while Dale Steyn (2-99), took two wickets in seven balls including that of Alastair Cook, who was bowled for 115 having added just a single to his overnight total.
Jacques Kallis claimed 2-38 and wicketkeeper AB de Villiers took five catches.
Scores: England: 385 (Alastair Cook 115, Jonathan Trott 71, Matt Prior 60; Morne Morkel 4-72, Jacques Kallis 2-38, Dale Steyn 2-99)
Teams:
England:
Andrew Strauss (captain), Alastair Cook, Jonathan Trott, Kevin Pietersen, Ian Bell, Ravi Bopara, Matt Prior, Tim Bresnan, Stuart Broad, Graeme Swann, James Anderson
South Africa:
Graeme Smith (captain), Alviro Petersen, Hashim Amla, Jacques Kallis, AB de Villiers, Jacques Rudolph, JP Duminy, Dale Steyn, Vernon Philander, Morné Morkel, Imran Tahir