Alastair Cook (46) and Essex team-mate Tom Westley (29) both fell with the score on 92 as England saw two wickets go down for no runs in 19 balls.
Dawid Malan helped England captain Joe Root put on 52 for the fourth wicket before, having battled hard, he fell to Morne Morkel for 18.
At tea, England were 147 for four, with star batsman Root 34 not out after winning the toss.
Ben Stokes, fresh from his man-of-the-match winning century in England's 239-run victory in the third Test at The Oval, was one not out after facing just three balls on Friday.
The hosts were making steady progress when former captain Cook tried to drive left-arm spinner Keshav Maharaj but instead got a thin edge to wicket-keeper Quinton de Kock.
Left-handed opener Cook, England's all-time leading Test run-scorer, faced 103 balls including six fours.
Westley, fresh from a second-innings fifty on debut at The Oval, scored 20 of his 29 runs in boundaries.
But he was undone by a good length delivery from fast bowler Kagiso Rabada that seamed and took the edge, with de Kock holding an excellent diving catch in his right glove.
Fast bowler Morkel has not always got the rewards he's deserved so far this series, but he saw off Malan when the Middlesex left-hander, born in London but raised in South Africa, edged a drive to Proteas captain Faf du Plessis at second slip. Morkel had tea figures of one for 34 in 13 overs.
England were unchanged from the side that triumphed in The Oval's 100th Test, a result that left Root on the brink of a win in his first series as England captain at 2-1 up with one to play.
But struggling opener Keaton Jennings, nearly caught and bowled by Rabada for four, fell for 17 to raise fresh questions about his England future ahead of this year's Ashes tour of Australia.
South Africa-born Jennings, under pressure for his place after just one fifty in nine Test innings since a century on debut against India in Mumbai in December, became the first of schoolboy team-mate De Kock's three dismissals so far this innings when he edged behind off Duanne Olivier.
Pace bowler Olivier and middle-order batsman Theunis de Bruyn were only playing as a result of Philander and Morris's injuries.
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